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

ABCG2 transporter inhibitor restores the sensitivity of triple negative breast cancer cells to aminolevulinic acid-mediated photodynamic therapy.

PubMed

Palasuberniam, Pratheeba; Yang, Xue; Kraus, Daniel; Jones, Patrick; Myers, Kenneth A; Chen, Bin

2015-08-18

Photosensitizer protoporphyrin IX (PpIX) fluorescence, intracellular localization and cell response to photodynamic therapy (PDT) were analyzed in MCF10A normal breast epithelial cells and a panel of human breast cancer cells including estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) positive and triple negative breast cancer (TNBC) cells after treatment with PpIX precursor aminolevulinic acid (ALA). Although PpIX fluorescence was heterogeneous in different cells, TNBC cells showed significantly lower PpIX level than MCF10A and ER- or HER2-positive cells. PpIX fluorescence in TNBC cells also had much less mitochondrial localization than other cells. There was an inverse correlation between PpIX fluorescence and cell viability after PDT. Breast cancer cells with the highest PpIX fluorescence were the most sensitive to ALA-PDT and TNBC cells with the lowest PpIX level were resistant to PDT. Treatment of TNBC cells with ABCG2 transporter inhibitor Ko143 significantly increased ALA-PpIX fluorescence, enhanced PpIX mitochondrial accumulation and sensitized cancer cells to ALA-PDT. Ko143 treatment had little effect on PpIX production and ALA-PDT in normal and ER- or HER2-positive cells. These results demonstrate that enhanced ABCG2 activity renders TNBC cell resistance to ALA-PDT and inhibiting ABCG2 transporter is a promising approach for targeting TNBC with ALA-based modality.

Cardiovascular photodynamic therapy: state of the art

NASA Astrophysics Data System (ADS)

Woodburn, Kathryn W.; Rockson, Stanley G.

2000-05-01

Photodynamic therapy (PDT) has been used traditionally for oncologic and ophthalmic indications. In addition, the enormous potential for the use of PDT agents in cardiovascular diseases is currently being translated into reality. Preclinical studies with various photosensitizers have demonstrated reduction in atheromatous plaque and prevention of intimal hyperplasia. With recent advances in light-based vascular devices and laser diode technology, the clinical use of cardiovascular photodynamic therapy is even more likely. Two photosensitizers, 5-aminolevulinic acid (ALA) and AntrinR (motexafin lutetium) Injection, are under clinical evaluation with many other agents in preclinical testing. Here, preclinical studies are reviewed and the clinical viability of cardiovascular photodynamic therapy is discussed.

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.

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.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

δ-Aminolevulinic acid transport in murine mammary adenocarcinoma cells is mediated by beta transporters

PubMed Central

Bermúdez Moretti, M; Correa García, S; Perotti, C; Batlle, A; Casas, A

2002-01-01

δ-aminolevulinic acid, the precursor of porphyrin biosynthesis has been used to induce the endogenous synthesis of the photosensitiser protoporphyrin IX for photodynamic therapy in the treatment of various tumours. The aim of this work was to characterise the δ-aminolevulinic acid transport system in the murine mammary adenocarcinoma cell line LM3 using 14C-δ-aminolevulinic acid, to finally improve δ-aminolevulinic acid incorporation in mammalian cells. Our results showed that δ-aminolevulinic acid is incorporated into these cells by two different mechanisms, passive diffusion which is important at the beginning of the incubation, and active transport. Specificity assays suggested that the transporter involved in δ-aminolevulinic acid incorporation is a BETA transporter, probably GAT-2. British Journal of Cancer (2002) 87, 471–474. doi:10.1038/sj.bjc.6600481 www.bjcancer.com © 2002 Cancer Research UK PMID:12177786

Vitamin D as a potential enhancer of aminolevulinate-based photodynamic therapy for nonmelanoma skin cancer

NASA Astrophysics Data System (ADS)

Maytin, Edward V.; Anand, Sanjay; Atanaskova, Natasha; Wilson, Clara

2010-02-01

Vitamin D3 (Vit D3) is a hormone essential for normal bone and cardiovascular health, and may participate in preventing nonmelanoma skin cancers (NMSC). Calcitriol (1,25 dihydroxyD3) is the active form of the hormone. We showed previously that calcitriol is a potent inducer of protoporphyrin IX (PpIX) in skin keratinocytes grown in organotypic cultures. Here, we investigated the ability of Vit D3 to enhance PpIX levels within skin tumors in vivo. Squamous tumors, generated by chemical carcinogenesis in mice, were pretreated for 3 days with topical calcitriol. Then 5-aminolevulinic acid (5-ALA) was applied topically, and PpIX levels were measured by noninvasive fluorimetry and in biopsied tissue. Calcitriol pretreatment resulted in a 3 to 4-fold elevation of PpIX in tumors, relative to no pretreatmen, providing significantly more photosensitizer available for tumor destruction. For deep tumors, topical calcitriol may not penetrate sufficiently. Therefore we explored whether systemic Vit D3, given short-term (3 days), might elevate PpIX within NMSC in a deep tumor model (subcutaneously-implanted A431 human squamous carcinoma cells). Defined amounts of calcitriol were injected into the mice for 3 d, followed by systemic 5-ALA, tissue biopsy, and confocal microscopic measurement of PpIX in frozen tissues. PpIX was clearly elevated after systemically delivered calcitriol. More work is needed, but if the amount of calcitriol required to elevate PpIX levels proves to be small, then the approach may ultimately prove attractive. Since most Americans are currently Vitamin D deficient, a small increase in calcitriol might be possible without risk of hypercalcemia.

Topical methotrexate pretreatment enhances the therapeutic effect of topical 5-aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers.

PubMed

Yang, Deng-Fu; Lee, Jeng-Woei; Chen, Hsin-Ming; Hsu, Yih-Chih

2014-09-01

Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical ALA-PDT alone (topical ALA-PDT group, n = 10). The intracellular protoporphyrin IX (PpIX) level in another 12 precancerous lesions (n = 6 for either the topical MTX-ALA or topical ALA group) was monitored by fluorescence spectroscopy. The intracellular PpIX reached its peak level in precancerous lesions 6.5 hours and 2.5 hours after topical ALA application for the topical MTX-ALA group (5.63-fold higher in the lesion than in the normal mucosa) and topical ALA group (2.42-fold higher in the lesion than in the normal mucosa), respectively. The complete response rate of precancerous lesions was 80% for the topical MTX-ALA-PDT group and 70% for the topical ALA-PDT group. In addition, the topical MTX-ALA-PDT group required a significantly lower mean treatment number (2.1 ± 0.6) to achieve complete response than the topical ALA-PDT group (4.4 ± 1.3, p < 0.001)). Moreover, the topical MTX-ALA-PDT group had a lower recurrence rate (12.5%) than the topical ALA-PDT group (28.6%). We conclude that topical MTX-pretreatment can increase intracellular PpIX production in hamster buccal pouch precancerous lesions and significantly improves the outcomes of the precancerous lesions treated with topical ALA-PDT. Copyright © 2014. Published by Elsevier B.V.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phung, Thu-Ha; Jung, Sunyo, E-mail: sjung@knu.ac.kr

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 redoxmore » 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.« less

In vitro study on methemoglobin formation in erythrocytes following hexyl-aminolevulinate induced photodynamic therapy

NASA Astrophysics Data System (ADS)

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

2007-02-01

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 hexyl-aminolevulinate (HAL) may increase the efficiency of PDT. HAL penetrates into the cell where the photosensitizer protoporphyrin IX (PPIX) is produced endogenously. In a previous study on HAL based PDT treatment of rat bladder cancer (AY-27 transitional cell carcinoma), a depression of the optical reflectance spectra after treatment was observed in some of the animals. This depression of the spectra was caused by metHemoglobin (metHb). MetHb is an indication of oxidative stress, and can be formed as a result of for instance UV-radiation and heating of blood. The aim of this study was to identify if metHb can be formed in vitro as a result of oxidative stress caused by singlet oxygen and ROS produced during PDT. Methemoglobin formed during PDT might thus be used as an indirect measure of the photochemical processes. This may help predict the PDT treatment outcome. Red blood cells mixed with AY-27 cells exposed to HAL, or PPIX received light treatment, and the changes in the absorption spectra were measured spectrophotometrically. The methemoglobin absorbance spectrum was also studied, and found to be strongly dependant on pH. Hemolysis of erythrocytes by PDT was found, however no metHb was formed in vitro.

Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid.

PubMed

Hillemanns, P; Untch, M; Dannecker, C; Baumgartner, R; Stepp, H; Diebold, J; Weingandt, H; Pröve, F; Korell, M

2000-03-01

Photodynamic (PDT) therapy is a relatively new technique with unique properties that make it attractive for the local treatment of superficial epithelial disorders. The objective of this study was to investigate the clinical response of PDT with the photosensitizing agent 5-aminolevulinic acid (5-ALA) in patients with vulvar intraepithelial neoplasia (VIN) grades 1 to 3. Twenty-five patients with 111 lesions of VIN 1-3 were topically sensitized with 10 ml of a 20% solution of 5-ALA and treated with 57 cycles of laser light at 635 nm (100 J/cm(2)). Seventy (64%) of the 111 VIN lesions regressed after various PDT cycles. A complete response was achieved in 13 patients (52%) with 27 lesions. All patients with VIN 1 and mono- and bifocal VIN 2-3 showed complete clearance. However, a complete response could be achieved in only 4 (27%) of 15 women with multifocal VIN 2-3, whereas a partial response was noted in 9 of these patients with a total of 70 lesions, out of which 44 (63%) lesions disappeared. No response was seen in 2 patients with multifocal VIN 3. Histological assessment of the fluorescence-directed biopsies revealed that increased pigmentation and hyperkeratosis of the lesions were associated with low response rates. PDT using 5-ALA represents an alternative treatment modality for VIN which is easy to perform and has the advantage of minimal tissue destruction, low side effects and excellent cosmetic results. However, multifocal VIN disease with pigmented and hyperkeratinic lesions remains difficult to treat. Copyright 2000 Wiley-Liss, Inc.

Methyl-aminolevulinate photodynamic therapy for the treatment of actinic cheilitis: a retrospective evaluation of 29 patients.

PubMed

Fai, D; Romano, I; Cassano, N; Vena, G A

2012-02-01

Multiple treatment modalities have been proposed for actinic cheilitis (AC), and topical photodynamic therapy (PDT) has recently been included among these modalities. We report our experience with PDT using methyl-aminolevulinate (MAL) in AC. We performed a retrospective analysis of 29 patients who had undergone MAL-PDT for treatment of AC: 4 patients received one single session and 25 patients two consecutive weekly sessions. At 3 months, 21 patients (72%) obtained a complete clinical response, which was sustained over a follow-up period of 6-36 months (mean, 20 months) in 20 patients. Cosmetic outcome was generally rated as good or very good. Transient local adverse events related to the procedure were common and mild to moderate in the majority of cases. Our preliminary experience suggests that MAL-PDT may be considered a valid modality for the treatment of AC, although long-term follow-up studies in large patient series are required to obtain precise data about clinical and histological recurrences.

Comparison of Physical Pretreatment Regimens to Enhance Protoporphyrin IX Uptake in Photodynamic Therapy: A Randomized Clinical Trial.

PubMed

Bay, Christiane; Lerche, Catharina Margrethe; Ferrick, Bradford; Philipsen, Peter Alshede; Togsverd-Bo, Katrine; Haedersdal, Merete

2017-04-01

Skin pretreatment is recommended for adequate penetration of topical photosensitizing agents and subsequent protoporphyrin IX (PPIX) accumulation in photodynamic therapy (PDT). To compare the relative potential of different physical pretreatments to enhance PPIX fluorescence in normal skin. This intraindividual, randomized clinical trial was performed from November 28 to December 20, 2014, at Bispebjerg Hospital, Copenhagen, Denmark, among 12 healthy volunteers 18 years or older. Analysis was based on intention to treat. All participants completed the study protocol. Participants were each exposed to standardized skin preparation with curettage, microdermabrasion with abrasive pads, microneedling with dermarollers, ablative fractional laser (AFXL), non-AFXL, and no pretreatment, followed by 3 hours of methyl aminolevulinate hydrochloride incubation and subsequent red light illumination. The primary outcome measure was methyl aminolevulinate-induced PPIX fluorescence accumulation. Secondary outcome measures were PPIX photobleaching and clinical local skin reactions, supported by noninvasive reflectance measurements of percentage of skin redness, transepidermal water loss, and participant-assessed pain. Among the 12 healthy study participants (8 men; 4 women; mean [SD] age, 33 [15] years), histologic findings confirmed standardization of interventions with partial removal of the stratum corneum after curettage and microdermabrasion and similar vertical penetration depths for microneedling, AFXL, and non-AFXL (median, 125 μm). PPIX fluorescence reached highest intensities in skin pretreated with AFXL (median, 8661 arbitrary units [AU]) compared with microdermabrasion (median, 6731 AU), microneedling (median, 5609 AU), and curettage (median, 4765 AU) (P < .001), among which similar enhancement was shown. Comparatively lower fluorescence levels were demonstrated for skin pretreated with non-AFXL (median, 2898 AU), methyl aminolevulinate-treated controls (median

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.

Randomized Vehicle-Controlled Study of Short Drug Incubation Aminolevulinic Acid Photodynamic Therapy for Actinic Keratoses of the Face or Scalp.

PubMed

Pariser, David M; Houlihan, Anna; Ferdon, Mary Beth; Berg, James E

2016-03-01

Aminolevulinic acid photodynamic therapy (ALA-PDT) can be effective and well tolerated when applied over a broad area and for short drug incubation times. To evaluate the effect of short-incubation time and application method on the safety and efficacy of ALA-PDT versus vehicle (VEH-PDT) in the treatment of actinic keratoses (AKs) of the face or scalp. Aminolevulinic acid or VEH was applied to face or scalp as a broad area application for 1, 2, or 3 hours or as a spot application for 2 hours before blue light activation. An identical treatment was repeated at Week 8 if any AK lesions remained. Median AK clearance rate for ALA-treated subjects ranged from 68% to 79% at Week 12, compared with 7% of the VEH-treated group (p < .0001). Complete clearance rate for ALA-treated subjects ranged from 17% (8/46) to 30% (14/47) at Week 12, compared with 2% (1/46) of the VEH-treated group (p = .0041). The safety profile seen in this study is consistent with previously reported side effects of the therapy. Short-incubation ALA-PDT was found to be superior to VEH-PDT for AK lesion clearance. A second treatment improves efficacy.

Plant Photodynamic Stress: What's New?

PubMed Central

Issawi, Mohammad; Sol, Vincent; Riou, Catherine

2018-01-01

In the 1970's, an unconventional stressful photodynamic treatment applied to plants was investigated in two directions. Exogenous photosensitizer treatment underlies direct photodynamic stress while treatment mediating endogenous photosensitizer over-accumulation pinpoints indirect photodynamic stress. For indirect photodynamic treatment, tetrapyrrole biosynthesis pathway was deregulated by 5-aminolevulenic acid or diphenyl ether. Overall, photodynamic stress involves the generation of high amount of reactive oxygen species leading to plant cell death. All these investigations were mainly performed to gain insight into new herbicide development but they were rapidly given up or limited due to the harmfulness of diphenyl ether and the high cost of 5-aminolevulinic acid treatment. Twenty years ago, plant photodynamic stress came back by way of crop transgenesis where for example protoporphyrin oxidases from human or bacteria were overexpressed. Such plants grew without dramatic effects of photodamage suggesting that plants tolerated induced photodynamic stress. In this review, we shed light on the occurrence of plant photodynamic stress and discuss challenging issues in the context of agriculture focusing on direct photodynamic modality. Indeed, we highlighted applications of exogenous PS especially porphyrins on plants, to further develop an emerged antimicrobial photodynamic treatment that could be a new strategy to kill plant pathogens without disturbing plant growth. PMID:29875786

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.

Topical versus systemic 5-aminolevulinic acid administration for photodynamic therapy of the colon in B10.RBP mice

NASA Astrophysics Data System (ADS)

Gil, Maciej; Woszczynski, Marek; Regula, Jaroslaw; MacRobert, Alexander J.; Butruk, Eugeniusz; Bown, Stephen G.

1999-07-01

5-aminolevulinic acid (5-ALA) is an interesting photosensitizing substance for photodynamic therapy (PDT), successfully applied topically for urological malignancy. In gastroenterology it has proven efficacy for treatment of some GI neoplasms after systemic administration. This study was aimed at investigating the possibility of topical 5-ALA administration also for the PDT of gut cancer in a mice model. 5-ALA solution at different concentrations (5%, 1.5%, and 0.5%) was instilled in the colon of mice, which was later removed and examined by fluorescence microscopy. The results of fluorescence studies were compared with those obtained in a control group treated with 5-ALA given systematically. Satisfactory epithelial fluorescence levels and good selectivity between gut layers were obtained after intracolonic 5-ALA instillation. However, mean fluorescence intensity was higher after systemic drug applications. Our results suggest that 5-ALA may probably be used topically for the PDT of some gut neoplasms.

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

NASA Astrophysics Data System (ADS)

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.

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.

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:

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.

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.

[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.

Perturbed porphyrin biosynthesis contributes to differential herbicidal symptoms in photodynamically stressed rice (Oryza sativa) treated with 5-aminolevulinic acid and oxyfluorfen.

PubMed

Phung, Thu-Ha; Jung, Sunyo

2014-11-01

This paper focuses on the molecular mechanism of deregulated porphyrin biosynthesis in rice plants under photodynamic stress imposed by an exogenous supply of 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). Plants treated with 5 mM ALA or 50 µM OF exhibited differential herbicidal symptoms as characterized by white and brown necrosis, respectively, with substantial increases in cellular leakage and malondialdehyde production. Protoporphyrin IX accumulated to higher levels after 1 day of ALA and OF treatment, whereas it decreased to the control level after 2 days of ALA treatment. Plants responded to OF by greatly decreasing the levels of Mg-protoporphyrin IX (MgProto IX), MgProto IX methyl ester, and protochlorophyllide to levels lower than control, whereas their levels drastically increased 1 day after ALA treatment and then disappeared 2 days after the treatment. Enzyme activity and transcript levels of HEMA1, GSA and ALAD for ALA synthesis greatly decreased in ALA- and OF-treated plants. Transcript levels of PPO1, CHLH, CHLI, and PORB genes involving Mg-porphyrin synthesis continuously decreased in ALA- and OF-treated plants, with greater decreases in ALA-treated plants. By contrast, up-regulation of FC2 and HO2 genes in Fe-porphyrin branch was noticeable in ALA and OF-treated plants 1 day and 2 days after the treatments, respectively. Decreased transcript levels of nuclear-encoded genes Lhcb1, Lhcb6, and RbcS were accompanied by disappearance of MgProto IX in ALA- and OF-treated plants after 2 days of the treatments. Under photodynamic stress imposed by ALA and OF, tight control of porphyrin biosynthesis prevents accumulation of toxic metabolic intermediates not only by down-regulation of their biosynthesis but also by photodynamic degradation. The up-regulation of FC2 and HO2 also appears to compensate for the photodynamic stress-induced damage. Copyright © 2014 Elsevier Inc. All rights reserved.

Assembly of catalase-based bioconjugates for enhanced anticancer efficiency of photodynamic therapy in vitro.

PubMed

Zhao, Jie; Fei, Jinbo; Du, Cuiling; Cui, Wei; Ma, Hongchao; Li, Junbai

2013-11-25

An oxygen generation core-shell structure uploading rose bengal has been fabricated by covalent assembly of catalase and alginate dialdehyde via Schiff's base. The composite can catalyze the decomposition of intracellular H2O2 to increase the concentration of O2, which effectively enhances the anticancer efficiency of photodynamic therapy in vitro.

Vitamin D Combined with Aminolevulinate (ALA)-Mediated Photodynamic Therapy (PDT) for Human Psoriasis: A Proof-of-Principle Study

PubMed Central

Maytin, Edward V.; Honari, Golara; Khachemoune, Amor; Taylor, Charles R.; Ortel, Bernhard; Pogue, Brian W.; Sznycer-Taub, Nathaniel; Hasan, Tayyaba

2012-01-01

We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis. PMID:23264699

Topical photodynamic therapy with 5-aminolevulinic acid in the treatment of actinic keratoses: a first clinical study

NASA Astrophysics Data System (ADS)

Karrer, Sigrid; Szeimies, Rolf-Markus; Sauerwald, Angela; Landthaler, Michael

1996-01-01

In this first clinical study performed according to GCP- (good clinical practice) guidelines, efficacy, and tolerability of topical photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) were tested in the treatment of actinic keratoses. Ten patients (6 f, 4 m) with 36 lesions (19 located on hands and arms, 17 on the head) received ALA-PDT once. Five to six hours after occlusive application of ALA (water-in-oil-emulsion containing 10% ALA) irradiation was performed with an incoherent light source. Up to 3 months after treatment patients were monitored. A score evaluating infiltration and keratosis of treated actinic keratoses allowed us to estimate therapeutic efficacy. Compared to the initial score (100%) significantly lower score-sums were observed at the 28 day follow-up at both localizations (head: 15%; hand: 67%). Complete remission (score sum 0) resulted in 71% of actinic keratoses localized on the head. Except for slight pain and burning sensations during and after irradiation there were no notable side effects. This study proved good efficacy and tolerability of topical PDT in the treatment of actinic keratoses. Whether PDT is able to compete with established treatment modalities remains to be shown in further studies.

5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

NASA Astrophysics Data System (ADS)

Maytin, Edward V.; Anand, Sanjay; Wilson, Clara; Iyer, Karthik

2011-02-01

5-Fluorouracil (5-FU) was developed in the 1950s as an anticancer drug and is now widely used to treat many cancers, including colon and breast carcinoma. 5-FU causes fluoronucleotide misincorporation into RNA and DNA, inhibits thymidylate synthase, and leads to growth arrest and apoptosis. For skin precancers (actinic keratoses; AK), 5-FU is prescribed as a topical agent and was essentially the only option for treating widespread AK of the skin prior to FDA approval of photodynamic therapy (PDT) in 1999. PDT is now gradually replacing 5-FU as a preferred treatment for AK, but neither PDT nor 5-FU are effective for true skin cancers (basal or squamous cell), particularly for tumors >1 mm in depth. In our ongoing work to improve the efficacy of PDT for skin cancer, we previously showed that PDT efficacy can be significantly enhanced by preconditioning tumors with methotrexate (MTX), which leads to increased production of protoporphyrin IX (PpIX) in target cells. However, because MTX must be given orally or intravenously, it is considered unacceptable for widespread human use due to potential toxicity. MTX and 5-FU exert similar effects on the thymidylate synthesis pathway, so we reasoned that topical 5-FU could be a potential alternative to MTX. In this paper, exploratory studies that test 5-FU as a preconditioning agent for PDT are presented. In a cutaneous model of squamous cell carcinoma (chemically-induced papillomatous tumors in mice), 5-FU significantly enhances PpIX accumulation and therefore emerges as a new candidate agent for combination therapy with PDT.

Potentiation of the photodynamic action of hypericin.

PubMed

Saw, Constance Lay Lay; Heng, Paul Wan Sia; Olivo, Malini

2008-01-01

Hypericin (HY) is an interesting photosensitizer with dark activity and photodynamic therapy (PDT) effects via p53-independent pathway. In photodynamic diagnosis (PDD) of bladder cancer using HY, very high sensitivity and specificity were reported, in comparison with its counterpart, 5-aminolevulinic acid (5-ALA). HY was tested for the detection of human gastric cancer. It was also studied for treating some cancers and age-related macular degeneration and showed some promising findings. Several strategies to enhance the efficacy of HY-PDD and HY-PDT are reviewed. Using fractionated light dosing, fractionated drug dosing, hyperthermia, adjuvants such as oxygen carrier/antiangiogenesis, chemical modifications, and formulation approaches to enhance the PDT effects of HY are topics of this review. Despite cutting-edge technology approach such as preparing transferring-mediated targeting HY liposomes and nanoparticles of HY, such preparations did not always offer the desired enhanced treatment effects. It turns out that simple solutions of HY, especially those prepared without using plasma protein, were more successful in enhancing the delivery of HY for in vitro and in vivo systems. Thus, the HY-PDT with these formulations performed better. It is anticipated that HY-PDD and HY-PDT can be enhanced and optimized with the right combination of light dosimetry and drug dose in an effective formulation containing a suitable adjuvant. Hyperoxygenation and hyperthermia can also be used to further enhance the efficacy of HY-PDT.

The effect of folic acid on porphyrin synthesis in tumors and normal skin of mice treated with 5-aminolevulinic acid or methyl 5-aminolevulinate.

PubMed

Ma, LiWei; Steindal, Arnfinn E; Juzeniene, Asta; Iani, Vladimir; Moan, Johan

2006-08-01

5-Aminolevulinic acid (ALA) or its derivative methyl 5-aminolevulinate (MAL) combined with folic acid was applied in nude mice bearing human colon adenocarcinoma. The aim of the study is to see whether folic acid may increase biosynthesis of porphyrins in tumor tissue after systemic or topical administration of ALA or MAL. The production of porphyrins was determined by spectrofluorometric measurements with an optical fibre probe. It was found that the porphyrin production after i.p injection of 200 mg kg(-1) ALA or MAL was significantly increased by i.p injection of 100 mg kg(-1) folic acid. However, in the case of topically applied 20% ALA, folic acid had no effect. In the case of topically applied 20% MAL, folic acid (i.p or topically applied) reduced the porphyrin synthesis. This might be used for the protection of normal skin against photosensitization. The effects of folic acid were similar in tumors and normal skin. Two mechanisms may explain the results: enhancement of the efficiency of the rate-limiting enzyme porphobilinogen deaminase by folic acid or interference of folic acid with the transport of ALA and MAL to and into the cells synthesizing porphyrins in the tissues. The present data seem to favour the latter mechanism. Folic acid may have a role as an adjuvant in photodynamic therapy with systemically administered ALA and its derivatives.

Consensus recommendations on the use of daylight photodynamic therapy with methyl aminolevulinate cream for actinic keratoses in Australia

PubMed Central

Shumack, Stephen; Murrell, Dedee F; Rubel, Diana M; Fernández‐Peñas, Pablo; Salmon, Robert; Hewitt, Daniel; Foley, Peter; Spelman, Lynda

2015-01-01

Abstract Australia has the highest prevalence of actinic keratoses (AK) worldwide. Because of the risk of transformation of AK to invasive squamous cell carcinomas, consensus guidelines recommend that AK are removed using appropriate therapies to prevent progression to invasive disease. Daylight photodynamic therapy (PDT) is emerging as an efficacious treatment for AK, particularly for patients who require treatment of large areas of chronic actinic damage that can be exposed easily to daylight. Daylight PDT with methyl aminolevulinate (MAL) cream is a simple treatment for AK, almost painless, well tolerated and convenient, requiring minimal time in the clinic. Randomised controlled studies from northern Europe and Australia support the use of daylight PDT as an effective therapy for grade I and II AK on the face and scalp. There is sufficient daylight to conduct daylight PDT in Australia at any time of the year and during most weather conditions. Hence, daylight PDT with MAL can be included as an effective and well‐tolerated new treatment option for the treatment of AK in Australia. These consensus recommendations provide guidelines for Australian clinicians on the use of daylight PDT in the treatment of diagnosed AK. PMID:26033230

Formulation and characterization of poly(ethylene glycol)-based, 5-aminolevulinic acid-loaded solid-dosage forms intended for photodynamic and photodiagnostic methodologies in the colorectal region.

PubMed

McCarron, Paul A; Andrews, Gavin P; Morrow, Desmond I J; Woolfson, A David; Donnelly, Ryan F

2007-01-01

Aminolevulinic acid-loaded, poly(ethylene glycol) disks prepared using three molecular weights (1000, 6000, and 10,000) were shown to be of potential for rectal administration as part of photodynamic and photodiagnostic colorectal procedures. The disk-shaped delivery system was mechanically robust, as judged by friability measurements. Calorimetric analysis confirmed that low concentrations of ALA (1% w/w) were dispersed completely throughout the PEG matrix, but higher concentrations (5% w/w and 10% w/w) formed crystalline suspensions. The molecular weight of the PEG determined the melting temperature, with PEG 1000 being suitable for melting around body temperature. The drug release kinetics were shown to be a function of both molecular weight and drug loading. Although the higher molecular weight PEG disks were resistant to surface erosion arising from an aqueous receptor phase, this effect was counterbalanced by more rapid and complete release when the ALA loading was increased. The lowest loading used (1% w/w) produced incomplete release, often not exceeding 30% of the total amount of drug. Results suggest that this simple formulation containing ALA can be administered directly to the colorectal area and is a feasible alternative to peroral dosing of ALA.

Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells

PubMed Central

Lee, Ming-Jen; Hung, Shih-Hsuan; Huang, Mu-Ching; Tsai, Tsuimin

2017-01-01

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo. PMID:28558025

Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells.

PubMed

Lee, Ming-Jen; Hung, Shih-Hsuan; Huang, Mu-Ching; Tsai, Tsuimin; Chen, Chin-Tin

2017-01-01

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.

Topical hexylaminolevulinate and aminolevulinic acid photodynamic therapy: complete arteriole vasoconstriction occurs frequently and depends on protoporphyrin IX concentration in vessel wall.

PubMed

Middelburg, T A; de Bruijn, H S; Tettero, L; van der Ploeg van den Heuvel, A; Neumann, H A M; de Haas, E R M; Robinson, D J

2013-09-05

Vascular responses to photodynamic therapy (PDT) may influence the availability of oxygen during PDT and the extent of tumor destruction after PDT. However, for topical PDT vascular effects are largely unknown. Arteriole and venule diameters were measured before and after hexylaminolevulinate (HAL) and aminolevulinic acid (ALA) PDT and related to the protoporphyrin IX (PpIX) concentration in the vessel wall. A mouse skin fold chamber model and an intravital confocal microscope allowed direct imaging of the subcutaneous vessels underlying the treated area. In both HAL and ALA groups over 60% of arterioles constricted completely, while venules generally did not respond, except for two larger veins that constricted partially. Arteriole vasoconstriction strongly correlated with PpIX fluorescence intensity in the arteriole wall. Total PpIX fluorescence intensity was significantly higher for HAL than ALA for the whole area that was imaged but not for the arteriole walls. In conclusion, complete arteriole vasoconstriction occurs frequently in both HAL and ALA based topical PDT, especially when relatively high PpIX concentrations in arteriole walls are reached. Vasoconstriction will likely influence PDT effect and should be considered in studies on topical HAL and ALA-PDT. Also, our results may redefine the vasculature as a potential secondary target for topical PDT. Copyright © 2013 Elsevier B.V. All rights reserved.

Activation of photodynamic therapy in vitro with Cerenkov luminescence generated from Yttrium-90 (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hartl, Brad A.; Hirschberg, Henry; Marcu, Laura; Cherry, Simon R.

2016-03-01

Translation of photodynamic therapy to the clinical setting has primarily been limited to easily accessible and/or superficial diseases where traditional light delivery can be performed noninvasively. Cerenkov luminescence, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively in order to overcome this depth limitation. We report on the use of Cerenkov luminescence generated from Yttrium-90 as a means to active the photodynamic therapy process in monolayer tumor cell cultures. The current study investigates the utility of Cerenkov luminescence for activating both the clinically relevant aminolevulinic acid at 1.0 mM and also the more efficient photosensitizer TPPS2a at 1.2 µM. Cells were incubated with aminolevulinic acid for 6 hours prior to radionuclide addition, as well as additional daily treatments for three days. TPPS2a was delivered as a single treatment with an 18 hour incubation time before radionuclide addition. Experiments were completed for both C6 glioma cells and MDA-MB-231 breast tumor cells. Although aminolevulinic acid proved ineffective for generating a therapeutic effect at any activity for either cell line, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 µCi/well for the C6 cell line. Current results demonstrate that it may be possible to generate a therapeutic effect in vivo using Cerenkov luminescence to activate the photodynamic therapy process with clinically relevant photosensitizers.

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.

Successful treatment of recalcitrant folliculitis barbae and pseudofolliculitis barbae with photodynamic therapy.

PubMed

Diernaes, Jon Erik Fraes; Bygum, Anette

2013-12-01

Folliculitis and pseudofolliculitis barbae typically affects men with curly hair who shave too close. Treatment modalities vary in effectiveness and include improved hair removal methods, topical corticosteroids, topical and oral antibiotics, and retinoids as well as laser surgery. We report a novel treatment of recalcitrant pseudofolliculitis barbae and confirm effectiveness in recalcitrant folliculitis in a 58-year old man who responded completely following photodynamic therapy with methyl aminolevulinate. Photodynamic therapy should be considered in recalcitrant folliculitis and pseudofolliculitis barbae. Copyright © 2013 Elsevier B.V. All rights reserved.

Smart pH-responsive upconversion nanoparticles for enhanced tumor cellular internalization and near-infrared light-triggered photodynamic therapy.

PubMed

Wang, Sheng; Zhang, Lei; Dong, Chunhong; Su, Lin; Wang, Hanjie; Chang, Jin

2015-01-01

A smart pH-responsive photodynamic therapy system based on upconversion nanoparticle loaded PEG coated polymeric lipid vesicles (RB-UPPLVs) was designed and prepared. These RB-UPPLVs which are promising agents for deep cancer photodynamic therapy applications can achieve enhanced tumor cellular internalization and near-infrared light-triggered photodynamic therapy.

Colloidal plasmonic gold nanoparticles and gold nanorings: shape-dependent generation of singlet oxygen and their performance in enhanced photodynamic cancer therapy.

PubMed

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

2018-01-01

In recognition of the potentials of gold nanoparticles (Au NPs) in enhanced photodynamic therapy (PDT) for cancer, it is desirable to further understand the shape-dependent surface plasmonic resonance (SPR) properties of various gold nanostructures and evaluate their performances in PDT. Monodispersed colloidal spherical solid Au NPs were synthesized by UV-assisted reduction using chloroauric acid and sodium citrate, and hollow gold nanorings (Au NRs) with similar outer diameter were synthesized based on sacrificial galvanic replacement method. The enhanced electromagnetic (EM) field distribution and their corresponding efficiency in enhancing singlet oxygen ( 1 O 2 ) generation of both gold nanostructures were investigated based on theoretical simulation and experimental measurements. Their shape-dependent SPR response and resulted cell destruction during cellular PDT in combination with 5-aminolevulinic acid (5-ALA) were further studied under different irradiation conditions. With comparable cellular uptake, more elevated formation of 1 O 2 in 5-ALA-enabled PDT was detected with the presence of Au NRs than that with Au NPs under broadband light irradiation in both cell-free and intracellular conditions. As a result of the unique morphological attributes, exhibiting plasmonic effect of Au NRs was still achievable in the near infrared (NIR) region, which led to an enhanced therapeutic efficacy of PDT under NIR light irradiation. Shape-dependent SPR response of colloidal Au NPs and Au NRs and their respective effects in promoting PDT efficiency were demonstrated in present study. Our innovative colloidal Au NRs with interior region accessible to surrounding photosensitizers would serve as efficient enhancers of PDT potentially for deep tumor treatment.

Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.

PubMed

Blake, E; Allen, J; Thorn, C; Shore, A; Curnow, A

2013-05-01

Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p<0.05) in PpIX fluorescence initially and both groups produced a significant decrease (p<0.05) after light irradiation. In conclusion, with this sample size, this OPI device was not found to be an effective method with which to improve tissue oxygenation during MAL-PDT. Further investigation is therefore required to find a more effective method of MAL-PDT enhancement.

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.

An In Vitro Model to Study the Effect of 5-Aminolevulinic Acid-mediated Photodynamic Therapy on Staphylococcus aureus Biofilm.

PubMed

Zhao, Ke-Qing; Wu, Yang; Yi, Yu-Xi; Feng, Si-Jia; Wei, Ruo-Yan; Ma, Ying; Zheng, Chun-Quan; Qu, Di

2018-04-16

Staphylococcus aureus (S. aureus) is a common human pathogen, which causes pyogenic and systemic infections. S. aureus infections are difficult to eradicate not only due to the emergence of antibiotic-resistant strains but also its ability to form biofilms. Recently, photodynamic therapy (PDT) has been indicated as one of the potential treatments for controlling biofilm infections. However, further studies are required to improve our knowledge of its effect on bacterial biofilms, as well as the underlying mechanisms. This manuscript describes an in vitro model of PDT with 5-aminolevulinic acid (5-ALA), a precursor of the actual photosensitizer, protoporphyrin IX (PpIX). Briefly, mature S. aureus biofilms were incubated with ALA and then exposed to light. Subsequently, the antibacterial effect of ALA-PDT on S. aureus biofilm was quantified by calculating the colony forming units (CFUs) and visualized by viability fluorescent staining via confocal laser scanning microscopy (CLSM). Representative results demonstrated a strong antibacterial effect of ALA-PDT on S. aureus biofilms. This protocol is simple and can be used to develop an in vitro model to study the treatment of S. aureus biofilms with ALA-PDT. In the future, it could also be referenced in PDT studies utilizing other photosensitizers for different bacterial strains with minimal adjustments.

Colloidal plasmonic gold nanoparticles and gold nanorings: shape-dependent generation of singlet oxygen and their performance in enhanced photodynamic cancer therapy

PubMed Central

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

2018-01-01

Introduction In recognition of the potentials of gold nanoparticles (Au NPs) in enhanced photodynamic therapy (PDT) for cancer, it is desirable to further understand the shape-dependent surface plasmonic resonance (SPR) properties of various gold nanostructures and evaluate their performances in PDT. Materials and methods Monodispersed colloidal spherical solid Au NPs were synthesized by UV-assisted reduction using chloroauric acid and sodium citrate, and hollow gold nanorings (Au NRs) with similar outer diameter were synthesized based on sacrificial galvanic replacement method. The enhanced electromagnetic (EM) field distribution and their corresponding efficiency in enhancing singlet oxygen (1O2) generation of both gold nanostructures were investigated based on theoretical simulation and experimental measurements. Their shape-dependent SPR response and resulted cell destruction during cellular PDT in combination with 5-aminolevulinic acid (5-ALA) were further studied under different irradiation conditions. Results With comparable cellular uptake, more elevated formation of 1O2 in 5-ALA-enabled PDT was detected with the presence of Au NRs than that with Au NPs under broadband light irradiation in both cell-free and intracellular conditions. As a result of the unique morphological attributes, exhibiting plasmonic effect of Au NRs was still achievable in the near infrared (NIR) region, which led to an enhanced therapeutic efficacy of PDT under NIR light irradiation. Conclusion Shape-dependent SPR response of colloidal Au NPs and Au NRs and their respective effects in promoting PDT efficiency were demonstrated in present study. Our innovative colloidal Au NRs with interior region accessible to surrounding photosensitizers would serve as efficient enhancers of PDT potentially for deep tumor treatment. PMID:29670350

Mechanism of enhanced responses after combination photodynamic therapy (cPDT) in carcinoma cells involves C/EBP-mediated transcriptional upregulation of the coproporphyrinogen oxidase (CPO) gene

NASA Astrophysics Data System (ADS)

Anand, Sanjay; Hasan, Tayyaba; Maytin, Edward V.

2013-03-01

Photodynamic therapy (PDT) with aminolevulinate (ALA) is widely accepted as an effective treatment for superficial carcinomas and pre-cancers. However, PDT is still suboptimal for deeper tumors, mainly due to inadequate ALA penetration and subsequent conversion to PpIX. We are interested in improving the effectiveness of photodynamic therapy (PDT) for deep tumors, using a combination approach (cPDT) in which target protoporphyrin (PpIX) levels are significantly enhanced by differentiation caused by giving Vitamin D or methotrexate (MTX) for 3 days prior to ALAPDT. In LNCaP and MEL cells, a strong correlation between inducible differentiation and expression of C/EBP transcription factors, as well as between differentiation and mRNA levels of CPO (a key heme-synthetic enzyme), indicates the possibility of CPO transcriptional regulation by the C/EBPs. Sequence analysis of the first 1300 base pairs of the murine CPO upstream region revealed 15 consensus C/EBP binding sites. Electrophoretic Mobility Shift Assays (EMSA) proved that these sites form specific complexes that have strong, moderate or weak affinities for C/EBPs. However, in the context of the full-length CPO promoter, inactivation of any type of site (strong or weak) reduced CPO promoter activity (luciferase assay) to nearly the same extent, suggesting cooperative interactions. A comparative analysis of murine and human CPO promoters revealed possible protein-protein interactions between C/EBPs and several neighboring transcription factors such as NFkB, Sp1, AP-1, CBP/p300 and CREB (an enhanceosome complex). Overall, these results confirm that C/EBP's are important for CPO expression via complex mechanisms which upregulate PpIX and enhance the outcome of cPDT.

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.

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.

Photodynamic therapy using a new formulation of 5-aminolevulinic acid for wrinkles in Asian skin: A randomized controlled split face study.

PubMed

Shin, Hyun Tae; Kim, Jun Hwan; Shim, Joonho; Lee, Jong Hee; Lee, Dong Youn; Lee, Joo Heung; Yang, Jun Mo

2015-06-01

Photodynamic therapy (PDT) with intense pulsed light (IPL) was proven effective for photorejuvenation. Recently, a new formulation of 0.5% 5-aminolevulinic acid (ALA) liposomal spray has been available. We designed a randomized split face study to evaluate usefulness and safety of IPL-PDT using a liposomal spray for periorbital wrinkles in Asians. Patients received three treatments every 3 weeks. The half of the face was treated with IPL-PDT and the other half with long pulsed Nd:YAG laser (LPNY). Skin fluorescence was measured using a spectrophotometer for the guidance of PDT treatment. Wrinkle score was marked by two-blinded independent dermatologists. One patient dropped out due to 3-d lasting erythema on PDT side. The difference of mean reduction in lower and lateral periorbital wrinkle score on PDT side between the first and the last visit was statistically significant (p = 0.008 and p = 0.001, respectively). Lateral periorbital wrinkles treated with PDT showed better results than LPNY-treated sides. Twenty-five percent of patients reported good to excellent outcomes. This study demonstrated that PDT with a liposomal spray provided modest wrinkle reduction without serious adverse effect and it might be a promising treatment modality for wrinkle treatment in Asians.

Spanish-Portuguese consensus statement on use of daylight-mediated photodynamic therapy with methyl aminolevulinate in the treatment of actinic keratosis.

PubMed

Gilaberte, Y; Aguilar, M; Almagro, M; Correia, O; Guillén, C; Harto, A; Pérez-García, B; Pérez-Pérez, L; Redondo, P; Sánchez-Carpintero, I; Serra-Guillén, C; Valladares, L M

2015-10-01

Daylight-mediated photodynamic therapy (PDT) is a new type of PDT that is as effective as conventional PDT in grade 1 and 2 actinic keratosis but with fewer adverse effects, resulting in greater efficiency. The climatic conditions in the Iberian Peninsula require an appropriately adapted consensus protocol. We describe a protocol for the treatment of grade 1 and 2 actinic keratosis with daylight-mediated PDT and methyl aminolevulinate (MAL) adapted to the epidemiological and clinical characteristics of Spanish and Portuguese patients and the climatic conditions of both countries. Twelve dermatologists from different parts of Spain and Portugal with experience in the treatment of actinic keratosis with PDT convened to draft a consensus statement for daylight-mediated PDT with MAL in these countries. Based on a literature review and their own clinical experience, the group developed a recommended protocol. According to the recommendations adopted, patients with multiple grade 1 and 2 lesions, particularly those at risk of developing cancer, are candidates for this type of therapy. Daylight-mediated PDT can be administered throughout the year, although it is not indicated at temperatures below 10°C or at excessively high temperatures. Likewise, therapy should not be administered when it is raining, snowing, or foggy. The procedure is simple, requiring application of a sunscreen with a protection factor of at least 30 based exclusively on organic filters, appropriate preparation of the lesions, application of MAL without occlusion, and activation in daylight for 2hours. This consensus statement represents a practical and detailed guideline to achieve maximum effectiveness of daylight-mediated PDT with MAL in Spain and Portugal with minimal adverse effects. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

The influence of photodynamic therapy (PDT) with δ-aminolevulinic acid (ALA) on J-774A.1 macrophage cell line

NASA Astrophysics Data System (ADS)

Kawczyk-Krupka, Aleksandra; Czuba, Zenon; Ledwon, Aleksandra; Latos, Wojciech; Sliszka, Ewelina; Mianowska, Marta; Krol, Wojciech; Sieron, Aleksander

2008-02-01

Introduction. The whole mechanism of the cellular level of tumor destruction by photodynamic therapy (PDT) is still unknown. Despite necrotic and apoptotic ways of cell death, there is a variety of events leading to and magnifying the inactivation of tumor cells. Material and methods. J-774A.1 were incubated with δ-aminolevulinic acid (ALA) at different concentrations (125, 250, 500, 1000 μM) and then irradiated with VIS (400 - 750 nm) at the dose of 5,10 and 30 J/cm2 delivered from the incoherent light source. The effects of the application of ALA-PDT were evaluated on the basis of cell viability, nitric oxide (NO), tumor necrosis factor α- (TNF-α) and interleukin-1β (IL-1β) produced by the J-774A.1 cells. Results. The cell viability (assessed using MTT test) was comparable with control group at 5,10 and 30 J/cm2. At these doses of energy using different concentrations of ALA we have observed that at the higher energy doses, the greater increase of TNF-α release, lowering of the level of IL-1β production and decrease of NO release were observed. There was also observed the dependence of the secretional activity of the cells on the ALA concentrations. Conclusion. The cell viability and production of cytokines depended on ALA concentrations and energy doses of the light. The higher some cytokines' release after PDT could be an additional factor for the complete eradication of tumor.

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.

Low-dose topical 5-aminolevulinic acid photodynamic therapy in the treatment of different severity of acne vulgaris.

PubMed

Ma, Li; Xiang, Lei-Hong; Yu, Bo; Yin, Rui; Chen, Lei; Wu, Yan; Tan, Zhi-Jian; Liu, Yong-Bin; Tian, Hong-Qing; Li, Hui-Zhong; Lin, Tong; Wang, Xiu-Li; Li, Yuan-Hong; Wang, Wei-Zheng; Yang, Hui-Lan; Lai, Wei

2013-12-01

To investigate the efficacy and safety of low-concentration 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of different severity of acne vulgaris and optimize the treatment regimen. A self-controlled multicenter clinical trial was carried out in 15 centers throughout China. A total of 397 acne patients of grade II-IV received 3- or 4-session PDT treatment. 5% ALA gel was applied topically to acne lesions for 1h incubation. The lesions were irradiated by a LED light of 633 nm at dose levels of 96-120 J/cm(2). Clinical assessment was conducted before and after every treatment up to 8 weeks. The effective rate overall and of grade II, III and IV are 82.1%, 71.6%, 79.6% and 88.2%, respectively. The effective rate rises significantly proportionally to the severity of acne (P<0.01). No significant differences are found in the efficacy between patients received 3-session and 4-session PDT treatments (P>0.05). The count of inflammatory and non-inflammatory acne lesions gradually decrease after each treatment (P<0.01) and during the 8-week follow up (P<0.01 or P<0.05). Maximum efficacy is obtained at 8 weeks after the treatment completion. A low-dose topical ALA-PDT regimen using 5% ALA, 1h incubation and red light source of 3 treatment sessions is suggested as optimal scheme for the treatment of different severity of acne vulgaris in Chinese patients. Superior efficacy is found in severe cystic acne of grade IV with mild side effects. Copyright © 2013 Elsevier B.V. All rights reserved.

5-Aminolevulinic acid loaded ethosomal vesicles with high entrapment efficiency for in vitro topical transdermal delivery and photodynamic therapy of hypertrophic scars.

PubMed

Zhang, Zheng; Chen, Yunsheng; Xu, Heng; Wo, Yan; Zhang, Zhen; Liu, Ying; Su, Weijie; Cui, Daxiang; Zhang, Yixin

2016-11-24

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for hypertrophic scars (HS), which destroys human hypertrophic scar fibroblasts (HSF). However, the poor permeability of ALA both in HS tissue and HSF significantly restricts the PDT of HS. To overcome these barriers, ALA-loaded ethosomal vesicles (ALA-ES) were developed by a pH gradient active loading method and characterized by morphology, entrapment efficiency (EE) and stability. Results show that prepared ALA-ES are homogenous spherical lamellar vesicles, 53 ± 7 nm in size, 50.6 ± 2.3% in EE and have excellent stability. In vitro transdermal delivery studies through HS tissue were carried out by using Franz diffusion cells. Compared to the traditional ALA hydroalcoholic solution (ALA-HA), ALA-ES achieve higher drug retention in less administration time, and fluorescence microscopy showed that ALA-ES penetrate into the deeper dermis of HS in a shorter time, indicating that ALA-ES can enhance the penetration of ALA into HS. Additionally, ALA-ES was visualized in HS tissue for the first time by transmission electron microscopy (TEM). The irregular and collapsed ALA-ES suggest that they can squeeze through narrow spaces to the target area and release ALA into HS. Taking HSF as the target, the transcellular delivery of ALA-ES into HSF cells was investigated by intracellular protoporphyrin IX (PpIX) accumulation. The efficiency of PDT for HSF cells, including the formation of reactive oxygen species (ROS) and cell apoptosis, were also well investigated. Furthermore, the detailed changes of HSF were observed by TEM. The results strongly indicate that ALA-ES can facilitate ALA penetration into HSF cells, and can cause a higher level of cell apoptosis or necrosis than ALA-HA. ALA-ES with high EE is therefore a promising transdermal delivery system for topical ALA administration and has great potential in ALA-PDT of HS.

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.

Randomized, Controlled Trial of Fractional Carbon Dioxide Laser Resurfacing Followed by Ultrashort Incubation Aminolevulinic Acid Blue Light Photodynamic Therapy for Actinic Keratosis.

PubMed

Alexiades, Macrene

2017-08-01

Aminolevulinic acid (ALA) photodynamic therapy (PDT) is an established treatment option for actinic keratosis (AK), and recently fractional carbon dioxide (CO2) laser was shown to improve outcomes; but studies of short incubation photosensitizer are lacking. Assess the efficacy of short incubation ALA followed by blue light PDT with and without previous fractional CO2 treatment for the treatment of AK. Randomized, paired split-design, controlled trial of fractional CO2 followed by ultrashort 15-minute versus 30-minute incubation ALA and blue light PDT for the treatment of AK on the face. The complete clearance rates (CRs) at 8 weeks after ALA PDT with and without FxCO2 at 30- and 15-minute ALA incubation times were 89.78% (+FxCO2) versus 71.20% CR (-FxCO2) at 30', and 86.38% (+FxCO2) versus 69.23% (-FxCO2) at 15' ALA incubation. All lesion improvements were statistically significant. This randomized, comparative paired group controlled clinical study demonstrates that ultrashort 15- and 30-minute incubation ALA PDTs are of limited efficacy for the treatment of AK. Pretreatment with fractional ablative resurfacing yields statistically significant greater AK clearance with ALA-PDT at ultrashort ALA incubations followed by blue light.

Photodynamic Therapy Interventions in Facial Photodamage: A Systematic Review.

PubMed

Sanclemente, G; Ruiz-Cañas, V; Miranda, J M; Ferrín, A P; Ramirez, P A; Hernandez, G N

2018-04-01

Photodynamic therapy (PDT) involves the combination of a light source and a photosensitizing agent to induce tissue damage via the generation of singlet oxygen. Although topical PDT has been approved for other indications, its use in facial photodamage is uncertain. To assess the efficacy and safety of PDT in facial skin photoaging. All randomized clinical trials (RCTs) evaluating the efficacy and safety of any form of topical PDT for the treatment of facial photodamage (dermatoheliosis) or photoaging in patients older than 18 years, were included. Photodynamic-therapy using any topical photosensitizing agent at any dose, and with any light-source, were considered. Comparators were chemical exfoliation, intense pulsed light (IPL), light emitting diodes (LED), dermabrasion or microdermabrasion, ablative or non-ablative lasers, injectables, surgery, placebo and/or no treatment. A systematic search in PubMed, Embase, Lilacs, Google Scholar and RCT's registry databases, was performed. Search was conducted up to May 4th 2016. Four authors independently selected and assessed methodological quality of each RCT. According to inclusion criteria, twelve studies were included (6 aminolevulinate (ALA) trials and 6 methyl aminolevulinate (MAL) trials), but the majority of them had methodological constraints particularly in randomization description and patients/outcome assessors blindness. Overall results indicated that PDT either with ALA or with MAL was effective and safe for facial photodamage treatment, but high quality of evidence was found mainly for MAL studies. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study.

PubMed

Pariser, David; Loss, Robert; Jarratt, Michael; Abramovits, William; Spencer, James; Geronemus, Roy; Bailin, Philip; Bruce, Suzanne

2008-10-01

The use of light-emitting diode light offers practical advantages in photodynamic therapy (PDT) with topical methyl-aminolevulinate (MAL) for management of actinic keratoses (AK). We sought to evaluate the efficacy of MAL PDT using red light-emitting diode light. We conducted a multicenter, double-blind, randomized study. A total of 49 patients with 363 AK lesions had 16.8% MAL cream applied under occlusion for 3 hours, and 47 patients with 360 AK lesions had vehicle cream similarly applied. The lesions were then illuminated (630 nm, light dose 37 J/cm2) with repeated treatment 1 week later. Complete lesion and patient (all lesions showing complete response) response rates were evaluated 3 months after last treatment. MAL PDT was superior (P<.0001) to vehicle PDT with respect to lesion complete response (86.2% vs 52.2%, odds ratio 6.9 [95% confidence interval 4.7-10.3]) and patient complete response (59.2% vs 14.9%, odds ratio 13.2 [95% confidence interval 4.1-43.1]). The study population may not be representative of all patients with AK. MAL PDT using red light-emitting diode light is an appropriate treatment alternative for multiple AK lesions.

Multifunctional nanoplatform for enhanced photodynamic cancer therapy and magnetic resonance imaging.

PubMed

Hao, Yongwei; Zhang, Bingxiang; Zheng, Cuixia; Niu, Mengya; Guo, Haochen; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong; Wang, Lei; Zhang, Yun

2017-03-01

Co-delivery of photosensitizers and synergistic agents by one single nanoplatform is interesting for enhancing photodynamic therapy (PDT) of cancer. Here, a multifunctional nanoplatform for enhanced photodynamic therapy and magnetic resonance imaging of cancer was constructed. The poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with hematoporphyrin monomethyl ether (HMME) were coated with multifunctional manganese dioxide (MnO 2 ) shells, which were designed as PLGA/HMME@MnO 2 NPs. Once the NPs were effectively taken up by tumor cells, the intracellular H 2 O 2 was catalysed by the MnO 2 shells to generate O 2 . Meanwhile, the higher glutathione (GSH) promoted the degradation of MnO 2 into Mn 2+ ions with the ability of magnetic resonance (MR) imaging. After the degradation of outer layer, the release of photosensitizer was promoted. Under irradiation, the released HMME produced cytotoxic reactive oxygen species (ROS) to damage the tumor cells when the O 2 was generated in the hypoxic tumor site. Furthermore, the decreased GSH level further inhibited the consumption of the produced ROS, which greatly enhanced the PDT efficacy. Therefore, this study suggested that this multifunctional system has the potential for enhanced photodynamic therapy and magnetic resonance imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

Can red-light 5-aminolevulinic photodynamic therapy cure port wine stains on comb animal model?

PubMed

Lai, Yongxian; Zhang, Haiyan; Wei, Minglei; Ji, Jie; Shi, Lei; Wang, Peiru; Wang, Bo; Huang, Zheng; Wang, Xiuli

2018-06-01

To study the curative effect of red-light 5-Aminolevulinic photodynamic therapy(ALA-PDT) to port wine stains(PWS) on comb animal model. 160 male cocks were randomly divided into 16 groups. The ALA only group was given ALA only topical or systemic application. Light only groups were only given 630 nm red light irradiation with different light density. ALA-PDT groups were given red light after the application of topical or systemic ALA. PDL group was given PDL irradiation. The distribution of fluorescence in tissue after topical or systemic application of ALA was detected. The morphological changes, the pathological changes and the capillary reduction rate of the comb were observed after treatment for 0, 1, 3, 5, 7, 14 days. The PpIX fluorescence generated after topical and systemic application of ALA. In the topical ALA-PDT group at low light density 80 J/cm 2 , the morphology and the histopathology had no obvious change. While under 160 J/cm 2 and 200 J/cm 2 light density, severe erosion and thick scab appeared. The histopathology showed epidermal necrosis and loss. The immunohistochemistry showed that there was no significant change in the number of capillaries under different light density (P > 0.05). In the systemic ALA-PDT group under low light density 80 J/cm 2 , only partial erosion and thin scab was observed on the treatment side. With the increase of light density, thick charred crust and even scar was observed. The histopathology showed that there were different degrees of damage to dermal and epidermal tissues. And the immunohistochemistry showed the capillary reduced significantly in the treatment side (P < 0.01). In control group, the comb is ruddy and plump. These results suggest that either topical or systemic red-light ALA-PDT is not suitable treatment methods for PWS. Copyright © 2018 Elsevier B.V. All rights reserved.

Is topical delta-aminolevulinic acid adequate for photodynamic therapy in Barrett's esophagus? A pilot study.

PubMed

Ortner, M -A; Zumbusch, K; Liebetruth, J; Ebert, B; Fleige, B; Dietel, M; Lochs, H

2002-08-01

The methods of endoscopic ablation of metaplastic and dysplastic areas in Barrett's esophagus so far described, are not satisfactory with respect to efficacy and safety. Therefore we investigated whether photodynamic therapy (PDT) with topical delta-aminolevulinic acid (delta-ALA) leads to ablation of specialized columnar epithelium and eradication of low-grade dysplasia while not producing phototoxicity and systemic side effects. 14 patients with histologically proven Barrett's esophagus, seven of whom had evidence of low-grade dysplasia, underwent endoscopic treatment with topical delta-ALA. Photoactivation (wavelength, 632 nm) was performed at 1.5 - 2 hours after drug administration using an argon dye laser. Patients received omeprazole 80 mg daily for 2 months; thereafter; maintenance therapy depended on reflux symptoms. Patients were endoscopically re-evaluated after 7 days, and subsequently at 3, 6, 12 and up to 48 months (mean follow up 33 months). Re-treatment with high-dose topical delta-ALA was offered to the 11 patients with remaining metaplasia and was carried out in five of them. Low-grade dysplasia was eradicated in all patients. One patient with no dysplasia before PDT developed a high-grade dysplasia after PDT. Complete ablation of Barrett's metaplasia was observed in 21 % of the patients after the first treatment session and in 20 % after the second treatment session. The mean reduction in the length of Barrett's metaplasia was 1.54 +/- 1.29 cm after the first PDT session and 1.02 +/- 0.80 cm after the second PDT session. Post-endoscopic pain and photosensitivity reactions were less frequent with low-dose delta-ALA PDT than with high-dose PDT (pain 15 %, 100 %, respectively; P = 0.001 by Fisher's exact test; phototoxicity, 0 %, 50 %, respectively; P = 0.021 by Fisher's exact test). Low-dose topical administration of delta-ALA provides ablation of low-grade dysplasia in the range obtained with oral delta-ALA. In addition, it is safe and well

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. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

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.

Photodynamic diagnosis (PDD) of bladder cancer with intravesical 5-aminolevulinic-acid-induced fluorescence

NASA Astrophysics Data System (ADS)

Grimbergen, Matthijs C. M.; Jonges, T. G. N.; Lock, M. Tycho W.; van Swol, Christiaan F. P.; Boon, Tom A.; van Moorselaar, R. Jeroen A.

2001-05-01

Flat urothelial lesions as well as small papillary tumors are easily missed during transurethral resection (TUR). PDD is based on the detection of protoporphyrin-IX induced fluorescence after topical administration of 5- aminolevulinic acid (ALA). We report on our initial clinical results of 130 procedures in 98 patients. Two hours prior to TUR 1.5 g ALA dissolved in 50 ml 1.4% NaHCO3 solution was installed intravesically. For fluorescence excitation a blue light source (375-440 nm, Karl Storz) was used. In total 478 biopsies (2-9 per patient) were taken from fluorescent and nonfluorescent areas. Normal nonfluorescent bladder urothelium was blue, whereas cancer epithelium developed a brilliant red fluorescence. During white light cystoscopy, 143 bladder tumors were found. Sixty-three additional tumors were detected because of their positive fluorescence. The overall sensitivity of fluorescence cystoscopy (98%) was greater than that of white light cystoscopy (69%). Their specificities were 51% and 80% respectively.

Mitochondria-targeted cationic porphyrin-triphenylamine hybrids for enhanced two-photon photodynamic therapy.

PubMed

Hammerer, Fabien; Poyer, Florent; Fourmois, Laura; Chen, Su; Garcia, Guillaume; Teulade-Fichou, Marie-Paule; Maillard, Philippe; Mahuteau-Betzer, Florence

2018-01-01

The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration. In addition the new compounds have been found localized in mitochondria that are preferential target organelles for photodynamic therapy. Altogether the strongly improved properties of the new series combined with their specific mitochondrial localization lead to a significantly enhanced two-photon activated photodynamic therapy efficiency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Potential efficacy of a delta 5-aminolevulinic acid thermosetting gel formulation for use in photodynamic therapy of lesions of the gastrointestinal tract.

PubMed

Bourre, Ludovic; Thibaut, Sonia; Briffaud, Amelie; Lajat, Youenn; Patrice, Thierry

2002-02-01

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX may play a role in the treatment of dysplastic Barrett's oesophagus. An ALA thermosetting gel Pluronic F-127) was developed and evaluated in an in vivo mouse model for potential use in PDT of Barrett's mucosa. In vitro studies of the influence of Pluronic F-127 percentage on thermosetting gel temperature, followed by the influence of ALA concentration on thermosetting temperature and ALA-gel stability as a function of time or temperature were studied. In vivo relationships between ALA doses and fluorescence were studied to determine the optimal concentration. Fluorescence measurement in vivo showed that ALA concentration and time had a nonlinear influence on protoporphyrin IX synthesis. For ALA-gel applications longer than 30 min a plateau fluorescence was reached, the maximum fluorescence being obtained after 4 h whatever the time of contact. The maximum intensity (2824 counts s(-1)) was found with 40 mg mL(-1) ALA-gel, and fluorescence intensities differed with time, reaching a maximum after 3-4 h. ALA-Pluronic F-127 is a suitable formulation for treatment of Barrett's oesophagus, allowing easy application in liquid form at 4 degrees C and good adhesion in the oesophagus in gel form, with efficient diffusion of ALA into treated mucosa. Copyright 2002 Elsevier Science Ltd.

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.

Electroporation enhances antimicrobial photodynamic therapy mediated by the hydrophobic photosensitizer, hypericin, Electroporation enhances antimicrobial photodynamic inactivation

PubMed Central

de Melo, Wanessa de Cássia Martins Antunes; Lee, Alexander N; Perussi, Janice Rodrigues; Hamblin, Michael R.

2013-01-01

The effective transport of photosensitizers (PS) across the membrane and the intracellular accumulation of PS are the most crucial elements in antimicrobial photodynamic therapy (aPDT). However, due to the morphological complexity of Gram-negative bacteria the penetration of PS is limited, especially hydrophobic PS. Electroporation (EP) could increase the effectiveness of aPDT, by promoting the formation of transient pores that enhance the permeability of the bacterial membrane to PS. In this study we evaluated the combination of aPDT mediated by the hydrophobic PS, hypericin and EP (aPDT/EP) against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. These bacteria were exposed to light (590 nm) in the presence of hypericin (4µM), following electroporation. The results showed that aPDT/EP inactivated 3.67 logs more E. coli and 2.65 logs more S. aureus than aPDT alone. Based on these results we suggest that EP can potentiate the aPDT effect. PMID:24284122

Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

NASA Astrophysics Data System (ADS)

Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

2005-04-01

During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

Idiopathic elastosis perforans serpiginosa with satisfactory response after 5-ALA photodynamic therapy.

PubMed

Alique-García, S; Company-Quiroga, J; Horcajada-Reales, C; Echeverría-García, B; Tardío-Dovao, J C; Borbujo, J

2018-03-01

Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light, and oxygen for the treatment of malignant or benign diseases. Topical photosensitizers employed in dermatology are 5-aminolevulinic acid (5 ALA) and methyl aminolevulinate, classically used for the treatment of superficial non-melanoma skin cancer and their precursors. Recently the efficacy of PDT has been introduced in other benign diseases. Elastosis perforans serpiginosa (EPS) is a rare skin disorder characterized by transepidermal elimination of abnormal elastic fibers. Management of this condition is complicated, various methods have been used but with limited success. We report a case of EPS in a 30-yeard-old woman treated with 5 ALA-PDT. After 4 sessions the lesions have almost completely disappeared with no residual side effects. Therefore we present an effective and safe alternative for the treatment of EPS. Copyright © 2017 Elsevier B.V. All rights reserved.

Delineating Normal from Diseased Brain by Aminolevulinic Acid-Induced Fluorescence

NASA Astrophysics Data System (ADS)

Stepp, Herbert; Stummer, Walter

5-Aminolevulinic acid (5-ALA) as a precursor of protoporphyrin IX (PpIX) has been established as an orally applied drug to guide surgical resection of malignant brain tumors by exciting the red fluorescence of PpIX. The accumulation of PpIX in glioblastoma multiforme (GBM) is highly selective and provides excellent contrast to normal brain when using surgical microscopes with appropriately filtered light sources and cameras. The positive predictive value of fluorescent tissue is very high, enabling safe gross total resection of GBM and other brain tumors and improving prognosis of patients. Compared to other intraoperative techniques that have been developed with the aim of increasing the rate of safe gross total resections of malignant gliomas, PpIX fluorescence is considerably simpler, more cost effective, and comparably reliable. We present the basics of 5-ALA-based fluorescence-guided resection, and discuss the clinical results obtained for GBM and the experience with the fluorescence staining of other primary brain tumors and metastases as well as the results for spinal cord tumors. The phototoxicity of PpIX, increasingly used for photodynamic therapy of brain tumors, is mentioned briefly in this chapter.

ALA-Butyrate prodrugs for Photo-Dynamic Therapy

NASA Astrophysics Data System (ADS)

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

2010-05-01

The use of 5-aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy (PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo-irradiation conditions showed that butyryloxyethyl 5-amino-4-oxopentanoate (ALA-BAC) generated the most efficient photodynamic destruction compared to ALA. ALA-BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA-BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA-BAC over ALA stems from its ability to induce photo-damage at a significantly lower dose than ALA.

Two-Step Irradiance Treatment Can Achieve Excellent Pain Control During Red Light 5-Aminolevulinic Acid Photodynamic Therapy for Actinic Keratoses.

PubMed

Paragh, Gyorgy; Zeitouni, Nathalie C

2018-03-01

To evaluate the ability of two-step irradiance to maintain pain control during red light 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) for actinic keratoses (AK) and assess factors influencing pain. PDT provides excellent clinical and cosmetic results in the treatment AK and early basal cell carcinomas (BCC). Widespread use of PDT is limited, in part, by pain. A two-step irradiance method for PDT has previously been shown to significantly reduce PDT-associated pain during the treatment of BCC, but the ability of this method to limit pain during the treatment of AKs has not been reported. We performed a retrospective chart review to assess the level of pain during AK treatment by red light PDT (n = 99). Natural density filter was used to reduce the irradiance of the light source and initially 10 J/cm 2 dose was delivered at 35 mW/cm 2 and then, 65 J/cm 2 dose was delivered at 70 mW/cm 2 . Pain level was measured using a 10-point visual analog scale at three points during the procedure. Pain was low to moderate in most patients (mean ± standard error of the mean pain score: 2.35 ± 0.19). Higher pain was seen midprocedure versus at the beginning (p < 0.0001) and at the end (p = 0.003) of PDT. There was no significant difference in pain perception between genders and different treatment areas. Our results provide evidence that red light ALA PDT of AKs is very well tolerated with the two-step irradiance protocol.

Recent advances in the prevention and treatment of skin cancer using photodynamic therapy

PubMed Central

Zhao, Baozhong; He, Yu-Ying

2011-01-01

Photodynamic therapy (PDT) is a noninvasive procedure that involves a photosensitizing drug and its subsequent activation by light to produce reactive oxygen species that specifically destroy target cells. Recently, PDT has been widely used in treating non-melanoma skin malignancies, the most common cancer in the USA, with superior cosmetic outcomes compared with conventional therapies. The topical ‘photosensitizers’ commonly used are 5-aminolevulinic acid (ALA) and its esterified derivative methyl 5-aminolevulinate, which are precursors of the endogenous photosensitizer protoporphyrin IX. After treatment with ALA or methyl 5-aminolevulinate, protoporphyrin IX preferentially accumulates in the lesion area of various skin diseases, which allows not only PDT treatment but also fluorescence diagnosis with ALA-induced porphyrins. Susceptible lesions include various forms of non-melanoma skin cancer such as actinic keratosis, basal cell carcinoma and squamous cell carcinoma. The most recent and promising developments in PDT include the discovery of new photosensitizers, the exploitation of new drug delivery systems and the combination of other modalities, which will all contribute to increasing PDT therapeutic efficacy and improving outcome. This article summarizes the main principles of PDT and its current clinical use in the management of non-melanoma skin cancers, as well as recent developments and possible future research directions. PMID:21080805

Non-toxic approach for treatment of breast cancer and its cutaneous metastasis: Capecitabine (Xeloda) enhanced photodynamic therapy in a murine tumor model

NASA Astrophysics Data System (ADS)

Anand, Sanjay; Denisyuk, Anton; Bullock, Taylor; Govande, Mukul; Maytin, Edward V.

2018-02-01

Breast cancer (BCA) is the most frequently diagnosed cancer in women, with distant metastases to lung, liver, bone and skin occurring in approximately 40% of cases. Radiation therapy (RT) has been successfully employed for the treatment of BCA; however, multiple rounds of RT are associated with undesirable cutaneous side effects. This study explores PDT as a therapeutic alternative, to be given alone or in combination with RT and chemotherapy. Earlier, we had developed differentiation-enhanced combination photodynamic therapy (cPDT) using a neoadjuvant (5-fluorouracil; 5FU) prior to PDT. The neoadjuvant increases the levels of PpIX, leading to better efficacy following aminolevulinate (ALA)- based PDT. Here, to avoid the toxicity of systemic 5FU, we used a nontoxic 5FU precursor (Capecitabine; CPBN) in a new cPDT regimen. CBPN, a standard chemotherapeutic for BCA, is metabolized to 5FU specifically within tumor tissue. Murine (4T1) BCA cells were injected into breast fat pads of nude mice. CPBN was administered by oral gavage followed by intraperitoneal ALA and red light for PDT. CPBN pretreatment of 4T1 tumors led to increased tumor cell differentiation (3.5 fold), homogenous elevation of intratumoral PpIX levels (4.5 fold), and enhanced tumor cell death post-PDT (5 fold), relative to vehicle control. Using an in vivo imaging system (IVIS), a decline in tumor growth following CPBN-PDT was observed. Results showing the effect of CPBN-PDT on distant metastases of BCA to lung, lymph nodes and skin will be presented. In summary, CPBN-PDT, a novel combination approach, has a significant potential for translation into the clinic.

Regulation of porphyrin synthesis and photodynamic therapy in heavy metal intoxication.

PubMed

Grinblat, Borislava; Pour, Nir; Malik, Zvi

2006-01-01

Protoporphyrin IX (PpIX) synthesis by malignant cells is successfully exploited for photodynamic therapy (PDT) following administration of 5-aminolevulinic acid (ALA) and light irradiation. The influence of two environmental heavy metal poisons, lead and gallium, on PpIX-synthesis and ALA-PDT was studied in two neu-ronal cell lines, SH-SY5Y neuroblastoma and PC12 pheochromocytoma. The heavy metal intoxication affected two of the heme-synthesis enzymes, ALA-dehydratase (ALAD) and porphobilinogen deaminase (PBGD). The present results show that lead poisoning significantly decreased the PBGD cellular level and inhibited its enzymatic activity, whereas the effects of gallium were less prominent. Although, the protein levels were reduced, the mRNA levels of PBGD remained unchanged during metal intoxication. These findings show additional inhibitory activity of lead on top of its classical effect on ALAD. Proteasome activity was enhanced during lead treatment, as measured by the AMC fluorigenic proteasome assay. The reduction in PBGD levels was not a consequence of PBGD mRNA reduced synthesis, which remained unchanged as shown by RT-PCR analysis. As a result of the lead poisoning, marked alterations in the cell cycle were observed, including a decreased G1 phase and an increased number of S phase cells. The efficacy of ALA-PDT was reduced in correlation with decreased activities of the enzymes during lead intoxication. We may conclude that lead poisoning adversely affects the outcome of ALA photodynamic therapy of cancer.

Evaluation of photodynamic treatment efficiency on glioblastoma cells received from malignant lesions: initial studies

NASA Astrophysics Data System (ADS)

Borisova, Ekaterina; Kyurkchiev, Dobroslav; Tumangelova-Yuzeir, Kalina; Angelov, Ivan; Genova-Hristova, Tsanislava; Semyachkina-Glushkovskaya, Oxana; Minkin, Krassimir

2018-04-01

Photodynamic therapy is well-established and extensively used method in treatment of different cancer types. This research reveals its potential in the treatment of cultivated human glioblastoma cells with adherent morphology. As the blood-brain barrier (BBB) permeability of the drugs is a significant problem that could not be solved easily for large biomolecules, we search for an appropriate low-molecular weight photosensitizer that could be applied for photodynamic treatment of glioblastoma cells. We used delta-aminolevulinic acid (5-ALA), which could pass BBB and plays the role of precursor of a protoporphyrin IX (PpIX) - photosensitizer, that is accumulated selectively in the tumour cells and could be a proper tool in PDT of glioblastoma. However, differences from patient to patient and between the cell activities could also lead to different effectiveness of the PDT treatment of the tumour areas. Therefore in our study we investigated not only the effect of using different fluence rates and light doses, but aims to establish more efficient values for further clinical applications for each sub-type of the GBM lesions. For the needs of PDT application an illumination device was developed in Laboratory of Biophotonics, BAS based on light-emitting diode (LED) matrix light sources for therapeutic application emitting at 635 nm. The device is optimized for PDT in combination with aminolevulinic acid/protoporphyrin IX applied as a photosensitizer drug. By the means of FACSCalibur flow cytometer (Becton Dickinson, USA) and Cell Quest Software was made evaluation of PDT effect on used human glioblastoma cells. Treatment of glioblastoma tumours continues to be a very serious issue and there is growing need in development of new concepts, methods and cancer-fighting strategies. PDT may contribute in accomplishing better results in cancer treatment and can be applied as well in combination with other techniques.

Comparison of cryotherapy and photodynamic therapy in treatment of oral leukoplakia.

PubMed

Kawczyk-Krupka, Aleksandra; Waśkowska, Jadwiga; Raczkowska-Siostrzonek, Agnieszka; Kościarz-Grzesiok, Anna; Kwiatek, Sebastian; Straszak, Dariusz; Latos, Wojciech; Koszowski, Rafał; Sieroń, Aleksander

2012-06-01

Oral leukoplakia is a pre-malignant lesion of the oral mucosa. The aim of this study is to compare the curative effects of photodynamic therapy and cryotherapy in the treatment of oral leukoplakia. The first group, treated by photodynamic therapy (δ-aminolevulinic acid (ALA), 630-635 nm wavelength), consisted of 48 patients suffering from leukoplakia. The second group consisted of 37 patients treated using cryotherapy. Analyses and comparisons of the complete responses, recurrences, numbers of procedures and adverse effects after both PDT and cryotherapy were obtained. In the first group, a complete response was obtained in 35 patients (72.9%), with thirteen recurrences observed (27.1%) over a six-month period. In the second group, a complete response was obtained in 33 patients (89.2%), and recurrence was observed in nine patients (24.3%). Photodynamic therapy and cryotherapy appear to be comparative methods of treatment that may both serve as alternatives for the traditional surgical treatment of oral leukoplakia. The advantages of PDT are connected with minimally invasive and localized character of the treatment and with not damage of collagenous tissue structures, therefore normal cells will repopulate these arrangements. PDT is more convenient for patients, less painful, and more esthetic. Copyright © 2011 Elsevier B.V. All rights reserved.

Amplifying the red-emission of upconverting nanoparticles for biocompatible clinically used prodrug-induced photodynamic therapy.

PubMed

Punjabi, Amol; Wu, Xiang; Tokatli-Apollon, Amira; El-Rifai, Mahmoud; Lee, Hyungseok; Zhang, Yuanwei; Wang, Chao; Liu, Zhuang; Chan, Emory M; Duan, Chunying; Han, Gang

2014-10-28

A class of biocompatible upconverting nanoparticles (UCNPs) with largely amplified red-emissions was developed. The optimal UCNP shows a high absolute upconversion quantum yield of 3.2% in red-emission, which is 15-fold stronger than the known optimal β-phase core/shell UCNPs. When conjugated to aminolevulinic acid, a clinically used photodynamic therapy (PDT) prodrug, significant PDT effect in tumor was demonstrated in a deep-tissue (>1.2 cm) setting in vivo at a biocompatible laser power density. Furthermore, we show that our UCNP-PDT system with NIR irradiation outperforms clinically used red light irradiation in a deep tumor setting in vivo. This study marks a major step forward in photodynamic therapy utilizing UCNPs to effectively access deep-set tumors. It also provides an opportunity for the wide application of upconverting red radiation in photonics and biophotonics.

Evaluation of the efficacy of photodynamic therapy for the treatment of actinic cheilitis.

PubMed

Chaves, Yuri N; Torezan, Luis Antonio; Lourenço, Silvia Vanessa; Neto, Cyro Festa

2017-01-01

Actinic cheilitis (AC) is a lip intraepithelial neoplasia, whose cells present alterations similar to those presented by invasive squamous cell carcinomas (SCCs). To conduct clinical and laboratory evaluation by histopathology and immunohistochemistry of the efficacy of actinic cheilitis treatment using photodynamic therapy (PDT) with methyl aminolevulinate (MAL) and noncoherent red light. Patients with actinic cheilitis detected by histopathological examination were submitted to two sessions of photodynamic therapy with a two-week interval between them. They were examined immediately after the sessions, four, six, and twelve weeks after beginning treatment when a new biopsy was carried out. Clinical histopathological and immunohistochemical parameters were evaluated before and after treatment. Of the 23 patients who underwent biopsy, 16 completed two photodynamic therapy sessions and the material of one patient was insufficient for immunohistochemistry. Complete clinical response was achieved in 62.5% (10 of 16 patients) and 37.5% still remained with clinical evidence of AC. In spite of this, no case of cure by histopathological analysis was found. There was no significant statistical change among the values of Ki-67, survivin, and p53 observed before and after treatment. Photodynamic therapy, as carried out in this trial, was not an efficacious therapeutic option for treating patients with actinic cheilitis included in this sample. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Topical photodynamic therapy with porphyrin precursors--assessment of treatment-associated pain in a retrospective study.

PubMed

Steinbauer, Julia Maria; Schreml, Stephan; Babilas, Philipp; Zeman, Florian; Karrer, Sigrid; Landthaler, Michael; Szeimies, Rolf-Markus

2009-08-01

Photodynamic therapy (PDT) with aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) is an approved modality for the non-invasive treatment of actinic keratoses (AK) and basal cell carcinoma (BCC) offering excellent cosmetic outcome. However, pain during and after illumination is the most frequent and limiting side effect. The aim of this study was to precisely assess how reported pain during PDT is influenced by sex, age, treatment site, disease (AK/BCC) as well as the photosensitizer used. 467 lesions consisting of AK (primary treatments: n=158; follow-up: n=47) or BCC (primary treatments: n=138; follow-up: 124) were treated by ALA- or MAL-PDT using metal halide lamps (580-750 nm). Pain was assessed during illumination using a continuous visual analogue scale (VAS). Factors predictive for higher pain levels during PDT are treatment of the head, treating AK and using ALA. The observed results may improve patient management and predict which level of pain to expect, and what kind of pain relief to prepare.

Activating Photodynamic Therapy in vitro with Cerenkov Radiation Generated from Yttrium-90

PubMed Central

Hartl, Brad A.; Hirschberg, Henry; Marcu, Laura; Cherry, Simon R.

2017-01-01

The translation of photodynamic therapy (PDT) to the clinical setting has primarily been limited to easily accessible and/or superficial diseases, for which traditional light delivery can be performed noninvasively. Cerenkov radiation, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively to overcome this depth limitation. This article investigates the utility of Cerenkov radiation, as generated from the radionuclide yttrium-90, for activating the PDT process using clinically approved aminolevulinic acid at 1.0 mm and also the more efficient porphyrin-based photosensitizer mesotetraphenylporphine with two sulfonate groups on adjacent phenyl rings (TPPS2a) at 1.2 μM. Experiments were conducted with monolayer cultured glioma and breast tumor cell lines. Although aminolevulinic acid proved to be ineffective for generating a therapeutic effect at all but the highest activity levels, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 μCi/well for the C6 glioma cell line. Importantly, these results demonstrate for the first time, to our knowledge, that Cerenkov radiation generated from a radionuclide can be used to activate PDT using clinically relevant photosensitizers. These results therefore provide evidence that it may be possible to generate a phototherapeutic effect in vivo using Cerenkov radiation and clinically relevant photosensitizers. PMID:27481495

Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy.

PubMed

Zhao, Yang; Zhang, Chenran; Gao, Liquan; Yu, Xinhe; Lai, Jianhao; Lu, Dehua; Bao, Rui; Wang, Yanpu; Jia, Bing; Wang, Fan; Liu, Zhaofei

2017-11-01

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. ©2017 AACR . ©2017 American Association for Cancer Research.

Amplifying the Red-Emission of Upconverting Nanoparticles for Biocompatible Clinically Used Prodrug-Induced Photodynamic Therapy

DOE PAGES

Punjabi, Amol; Wu, Xiang; Tokatli-Apollon, Amira; ...

2014-09-25

A class of biocompatible upconverting nanoparticles (UCNPs) with largely amplified red-emissions was developed. The optimal UCNP shows a high absolute upconversion quantum yield of 3.2% in red-emission, which is 15-fold stronger than the known optimal β-phase core/shell UCNPs. When conjugated to aminolevulinic acid, a clinically used photodynamic therapy (PDT) prodrug, significant PDT effect in tumor was demonstrated in a deep-tissue (>1.2 cm) setting in vivo at a biocompatible laser power density. Furthermore, we show that our UCNP–PDT system with NIR irradiation outperforms clinically used red light irradiation in a deep tumor setting in vivo. This study marks a major stepmore » forward in photodynamic therapy utilizing UCNPs to effectively access deep-set tumors.Lastly, it also provides an opportunity for the wide application of upconverting red radiation in photonics and biophotonics.« less

Amplifying the Red-Emission of Upconverting Nanoparticles for Biocompatible Clinically Used Prodrug-Induced Photodynamic Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Punjabi, Amol; Wu, Xiang; Tokatli-Apollon, Amira

A class of biocompatible upconverting nanoparticles (UCNPs) with largely amplified red-emissions was developed. The optimal UCNP shows a high absolute upconversion quantum yield of 3.2% in red-emission, which is 15-fold stronger than the known optimal β-phase core/shell UCNPs. When conjugated to aminolevulinic acid, a clinically used photodynamic therapy (PDT) prodrug, significant PDT effect in tumor was demonstrated in a deep-tissue (>1.2 cm) setting in vivo at a biocompatible laser power density. Furthermore, we show that our UCNP–PDT system with NIR irradiation outperforms clinically used red light irradiation in a deep tumor setting in vivo. This study marks a major stepmore » forward in photodynamic therapy utilizing UCNPs to effectively access deep-set tumors.Lastly, it also provides an opportunity for the wide application of upconverting red radiation in photonics and biophotonics.« less

21 CFR 862.1060 - Delta-aminolevulinic acid test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... poisoning and certain porphyrias (diseases affecting the liver, gastrointestinal, and nervous systems that... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Delta-aminolevulinic acid test system. 862.1060... Systems § 862.1060 Delta-aminolevulinic acid test system. (a) Identification. A delta-aminolevulinic acid...

21 CFR 862.1060 - Delta-aminolevulinic acid test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... poisoning and certain porphyrias (diseases affecting the liver, gastrointestinal, and nervous systems that... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Delta-aminolevulinic acid test system. 862.1060... Systems § 862.1060 Delta-aminolevulinic acid test system. (a) Identification. A delta-aminolevulinic acid...

21 CFR 862.1060 - Delta-aminolevulinic acid test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... poisoning and certain porphyrias (diseases affecting the liver, gastrointestinal, and nervous systems that... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Delta-aminolevulinic acid test system. 862.1060... Systems § 862.1060 Delta-aminolevulinic acid test system. (a) Identification. A delta-aminolevulinic acid...

21 CFR 862.1060 - Delta-aminolevulinic acid test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... poisoning and certain porphyrias (diseases affecting the liver, gastrointestinal, and nervous systems that... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Delta-aminolevulinic acid test system. 862.1060... Systems § 862.1060 Delta-aminolevulinic acid test system. (a) Identification. A delta-aminolevulinic acid...

21 CFR 862.1060 - Delta-aminolevulinic acid test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... poisoning and certain porphyrias (diseases affecting the liver, gastrointestinal, and nervous systems that... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Delta-aminolevulinic acid test system. 862.1060... Systems § 862.1060 Delta-aminolevulinic acid test system. (a) Identification. A delta-aminolevulinic acid...

Efficacy of ultra short sub-30 minute incubation of 5-aminolevulinic acid photodynamic therapy in vitro.

PubMed

Koo, Eugene; Austin, Evan; Mamalis, Andrew; Jagdeo, Jared

2017-08-01

The estimated incidence of cutaneous squamous cell carcinoma (SCC) is 700,000 cases per year. In the US, SCC incidence is highest among fair skinned adults older than 50 years of age. Thus, as the population ages, the reported number of SCCs will likely increase in the future. Photodynamic therapy (PDT) is an FDA approved therapy for treatment of actinic keratoses (AKs), a precursor to cutaneous SCC lesions. The FDA approved incubation time of the photosensitizing agent 5-aminolevulinic acid (ALA) is 14-18 hours. Recent studies have investigated short ALA incubation times of 1-3 hours with ALA and PDT demonstrating treatment success. Therefore, the question exists whether ALA incubation periods of less than 30 minutes are efficacious. Herein, we evaluate the efficacy of short ALA incubation periods by measuring apoptosis after 10, 15, and 20 minutes of ALA incubation. AG13145 normal human dermal fibroblasts HDFs were incubated with 10, 15, or 20 minute of ALA at various concentrations (0, 0.05, 0.075, 0.1, 0.25, 0.375, 0.5, 1, and 2 mM). After ALA incubation, samples were treated with 1,000 seconds (16 minutes 40 seconds) of Blu-U fluorescent blue light (417 ± 5 nm) for a fluence of 10 J/cm 2 . Immediately following treatment with blue light, samples were collected and stained for apoptosis and necrosis with annexin-V and 7-aminoactinomycin D (7-AAD), and then analyzed by flow cytometry. HDFs incubated with ALA for 10 minute at 36 °C followed by 10 J/cm 2 of blue light had no statistically significant changes in apoptosis. HDFs incubated with ALA for 15 or 20 minutes at 36 °C followed by 10 J/cm 2 of blue light had statistically significant increases in the percentages of cells positive for apoptosis in the 0.5, 1.0, and 2.0 mM ALA doses (P < 0.05). We found that incubation of ALA for at least 15 minutes followed by 10 J/cm 2 of blue light resulted in a statistically significant increase in apoptosis. Lasers Surg. Med. 49

Photodynamic diagnosis following intravesical instillation of aminolevulinic acid (ALA): first clinical experiences in urology

NASA Astrophysics Data System (ADS)

Baumgartner, Reinhold; Kriegmair, M.; Stepp, Herbert G.; Lumper, W.; Heil, Peter; Riesenberg, Rainer; Stocker, Susanne; Hofstetter, Alfons G.

1993-06-01

Delta Aminolevulinic acid (ALA), a precursor of Protoporphyrin IX (PP IX) in hem biosynthesis has been topically applied in urinary bladders in order to study its potential as fluorescent tumor marker. Preclinical experiments have been performed on chemically induced tumors in rats, revealing a ratio of PP IX-fluorescence intensity up to 20:1 in tumors as compared to healthy urothelium. Synthesis of PP IX has been stimulated in 56 patients by intravesical instillation of a pH-neutral ALA-solution. After an incubation time of two to four hours strong red fluorescence was endoscopically observed even in tiny superficial tumors. Brightness and contrast allows visualization of early stage urothelial diseases with naked eyes and without the necessity suppressing background fluorescence or violet excitation light.

Biochemical transformation of mouse cells by herpes simplex virus type 2: enhancement by means of low-level photodynamic treatment.

PubMed Central

Verwoerd, D W; Rapp, F

1978-01-01

The biochemical transformation of thymidine kinase-deficient cells by UV-inactivated herpes simplex virus is enhanced by low-level photodynamic treatment of the infected cells. At the concentration of proflavine used, the virus was not inactivated and both virus and cellular DNA syntheses were only marginally inhibited. The observed enhancement of the transfer of a virus gene to the cell genome suggests a possible cocarcinogenic role for photodynamically active dyes at very low concentrations. PMID:206727

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.

Comparative study of the bactericidal effects of 5-aminolevulinic acid with blue and red light on Propionibacterium acnes.

PubMed

Choi, Myoung-Soon; Yun, Sook Jung; Beom, Hee Ju; Park, Hyoung Ryun; Lee, Jee-Bum

2011-07-01

Propionibacterium acnes naturally produces endogenous porphyrins that are composed of coproporphyrin III (CPIII) and protoporphyrin IX (PpIX). Red light alone and photodynamic therapy (PDT) improve acne vulgaris clinically, but there remains a paucity of quantitative data that directly examine the bactericidal effects that result from PDT on P. acnes itself in vitro. The purpose of this study was to measure the difference of bactericidal effects of 5-aminolevulinic acid (ALA)-PDT with red and blue light on P. acnes. P. acnes were cultured under anaerobic conditions and divided into two groups (ALA-treated group and control group), and were then illuminated with blue (415 nm) and red (635 nm) lights using a light-emitting diode (LED). The cultured P. acnes were killed with both blue and red LED light illumination. The efficacy increased with larger doses of light and a greater number of consecutive illuminations. We demonstrated that red light phototherapy was less effective for the eradication of P. acnes than blue light phototherapy without the addition of ALA. However, pretreatment with ALA could enhance markedly the efficacy of red light phototherapy. © 2010 Japanese Dermatological Association.

Surgery combined with local 5-aminolevulinic acid-photodynamic therapy on skin cancer and its effect on the expression of cyclophilin A, cyclophilin B and CD147

PubMed Central

Guo, Ling; Han, Yingsheng

2017-01-01

The study evaluated an approach to treat skin cancer using surgery combined with local 5-aminolevulinic acid-photodynamic therapy (ALA-PDT). Seventy-six patients with skin cancer who were admitted to the Liaocheng People's Hospital from May 2014 to April 2015 were randomly divided into a control and an observation group (38 cases in each). The patients in the control group were treated with ALA-PDT alone. Those in the observation group were first subjected to surgical treatment, and then treated with ALA-PDT. The treatment efficacies of the two groups were compared. The expression of cancer markers CyPA, CyPB and CD147 were detected by immunohistochemical methods before and after the treatment. Our results showed the average healing time of the wounds of patients in the observation group was shorter, the number of treatments needed was less, the efficacy rate and the lesion appearance satisfaction were significantly higher, and the recurrence rate at 12 months after treatment and the incidence of adverse reactions were both significantly lower. Additionally, the levels of CyPA, CyPB and CD147 were reduced to a significantly higher degree after treatment in the observation group. No difference was found in the recurrence rate between the two groups at 6 months after treatment. We conclude that surgery combined with ALA-PDT is a safe and reliable treatment method, which can increase the survival rate while improving the recovery rate and appearance satisfaction in patients with skin cancer. PMID:28789363

Surgery combined with local 5-aminolevulinic acid-photodynamic therapy on skin cancer and its effect on the expression of cyclophilin A, cyclophilin B and CD147.

PubMed

Guo, Ling; Han, Yingsheng

2017-08-01

The study evaluated an approach to treat skin cancer using surgery combined with local 5-aminolevulinic acid-photodynamic therapy (ALA-PDT). Seventy-six patients with skin cancer who were admitted to the Liaocheng People's Hospital from May 2014 to April 2015 were randomly divided into a control and an observation group (38 cases in each). The patients in the control group were treated with ALA-PDT alone. Those in the observation group were first subjected to surgical treatment, and then treated with ALA-PDT. The treatment efficacies of the two groups were compared. The expression of cancer markers CyPA, CyPB and CD147 were detected by immunohistochemical methods before and after the treatment. Our results showed the average healing time of the wounds of patients in the observation group was shorter, the number of treatments needed was less, the efficacy rate and the lesion appearance satisfaction were significantly higher, and the recurrence rate at 12 months after treatment and the incidence of adverse reactions were both significantly lower. Additionally, the levels of CyPA, CyPB and CD147 were reduced to a significantly higher degree after treatment in the observation group. No difference was found in the recurrence rate between the two groups at 6 months after treatment. We conclude that surgery combined with ALA-PDT is a safe and reliable treatment method, which can increase the survival rate while improving the recovery rate and appearance satisfaction in patients with skin cancer.

Photochemical predictive analysis of photodynamic therapy with non-homogeneous topical photosensitizer distribution in dermatological applications

NASA Astrophysics Data System (ADS)

Salas-García, I.; Fanjul-Vélez, F.; Ortega-Quijano, N.; López-Escobar, M.; Arce-Diego, J. L.

2010-04-01

Photodynamic Therapy (PDT) is a therapeutic technique widely used in dermatology to treat several skin pathologies. It is based in topical or systemic delivery of photosensitizing drugs followed by irradiation with visible light. The subsequent photochemical reactions generate reactive oxygen species which are considered the principal cytotoxic agents to induce cell necrosis. In this work we present a PDT model that tries to predict the photodynamic effect on the skin with a topically administered photosensitizer. The time dependent inhomogeneous distribution of the photoactive compound protoporphyrin IX (PpIX) is calculated after obtaining its precursor distribution (Methyl aminolevulinate, MAL) which depends on the drug permeability, diffusion properties of the skin, incubation time and conversion efficiency of MAL to PpIX. Once the optical energy is obtained by means of the Beer Lambert law, a photochemical model is employed to estimate the concentration of the different molecular compounds taking into account the electronic transitions between molecular levels and particles concentrations. The results obtained allow us to know the evolution of the cytotoxic agent in order to estimate the necrotic area adjusting parameters such as the optical power, the photosensitizer concentration, the incubation and exposition time or the diffusivity and permeability of the tissue.

Plasmonic enhancement of cyanine dyes for near-infrared light-triggered photodynamic/photothermal therapy and fluorescent imaging

NASA Astrophysics Data System (ADS)

Lu, Mindan; Kang, Ning; Chen, Chuan; Yang, Liuqing; Li, Yang; Hong, Minghui; Luo, Xiangang; Ren, Lei; Wang, Xiumin

2017-11-01

Near-infrared (NIR) triggered cyanine dyes have attracted considerable attention in multimodal tumor theranostics. However, NIR cyanine dyes used in tumor treatment often suffer from low fluorescence intensity and weak singlet oxygen generation efficiency, resulting in inadequate diagnostic and therapy efficacy for tumors. It is still a great challenge to improve both the photodynamic therapy (PDT) and fluorescent imaging (FLI) efficacy of cyanine dyes in tumor applications. Herein, a novel multifunctional nanoagent AuNRs@SiO2-IR795 was developed to realize the integrated photothermal/photodynamic therapy (PTT/PDT) and FLI at a very low dosage of IR795 (0.4 μM) based on metal-enhanced fluorescence (MEF) effects. In our design, both the fluorescence intensity and reactive oxygen species of AuNRs@SiO2-IR795 nanocomposites were significantly enhanced up to 51.7 and 6.3 folds compared with free IR795, owing to the localized surface plasmon resonance band of AuNRs overlapping with the absorption or fluorescence emission band of the IR795 dye. Under NIR laser irradiation, the cancer cell inhibition efficiency in vitro with synergetic PDT/PTT was up to 82.3%, compared with 10.3% for free IR795. Moreover, the enhanced fluorescence intensity of our designed nanocomposites was helpful to track their behavior in tumor cells. Therefore, our designed nanoagents highlight the applications of multimodal diagnostics and therapy in tumors based on MEF.

Topical photodynamic therapy with 5-ALA in the treatment of arsenic-induced skin tumors

NASA Astrophysics Data System (ADS)

Karrer, Sigrid; Szeimies, Rolf-Markus; Landthaler, Michael

1995-03-01

A case of a 62-year-old woman suffering from psoriasis who was treated orally with arsenic 25 years ago is reported. The cumulative dose of arsenic trioxide was 800 mg. Since 10 years ago arsenic keratoses, basal cell carcinomas, Bowen's disease and invasive squamous cell carcinomas mainly on her hands and feet have developed, skin changes were clearly a sequence of arsenic therapy. Control of disease was poor, her right little finger had to be amputated. Topical photodynamic therapy with 5-aminolevulinic acid was performed on her right hand. Clinical and histological examinations 6 months after treatment showed an excellent cosmetic result with no signs of tumor residue.

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.

Photodynamic therapy: Theoretical and experimental approaches to dosimetry

NASA Astrophysics Data System (ADS)

Wang, Ken Kang-Hsin

fluorescence spectroscopy. We successfully simulate the in vivo photobleaching of PpIX in this patient population over a wide range of irradiances using the PDT model. For most cases, the rate of bleaching slows as treatment progresses, leaving a fraction of the PpIX unbleached despite sustained irradiation. To account for this feature, the model predicts that incorporation of ALA-PDT-induced blood flow reduction is necessary. In addition to using the theoretical method to understand the dose deposited by photodynamic therapy, experimentally, we propose a potential dose metric for Pc 4-PDT. Pc 4 is a promising second generation photosensitizer that is now in Phase I clinical trials for the treatment of cutaneous lesions. We have observed a significant irradiation-induced increase in Pc 4 fluorescence in tumor cell monolayers. The amount of the fluorescence increase observed in vitro strongly correlates to the cell death and mitochondrial swelling reported by the clonogenic cell survival assay and light scattering measurements, respectively. Based on those biological responses, we anticipate that irradiation-induced fluorescence enhancement in Pc 4-PDT may be a potential dose metric.

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

Photodynamic Cancer Therapy - Recent Advances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abrahamse, Heidi

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 ormore » 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

Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source.

PubMed

Namikawa, Tsutomu; Fujisawa, Kazune; Munekage, Eri; Iwabu, Jun; Uemura, Sunao; Tsujii, Shigehiro; Maeda, Hiromichi; Kitagawa, Hiroyuki; Fukuhara, Hideo; Inoue, Keiji; Sato, Takayuki; Kobayashi, Michiya; Hanazaki, Kazuhiro

2018-04-04

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.

[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.

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.

A Nanosystem Capable of Releasing a Photosensitizer Bioprecursor under Two‐Photon Irradiation for Photodynamic Therapy

PubMed Central

Wu, Hao; Zeng, Fang; Zhang, Hang; Xu, Jiangsheng

2015-01-01

The applications of photodynamic therapy (PDT) are usually limited by photosensitizers' side effects and singlet oxygen's short half‐life. Herein, a mitochondria‐targeted nanosystem is demonstrated to enhance the PDT efficacy by releasing a bio‐precursor of photosensitizer under two‐photon irradiation. A phototriggerable coumarin derivative is first synthesized by linking 5‐aminolevulinic acid (5‐ALA, the bio‐precursor) to coumarin; and the nanosystem (CD‐ALA‐TPP) is then fabricated by covalently incorporating this coumarin derivative and a mitochondria‐targeting compound triphenylphosphonium (TPP) onto carbon dots (CDs). Upon cellular internalization, the nanosystem preferentially accumulates in mitochondria; and under one‐ or two‐photon irradiation, it releases 5‐ALA molecules that are then metabolized into protoporphyrin IX in mitochondria through a series of biosynthesis processes. The subsequent red light irradiation induces this endogenously synthesized photosensitizer to generate singlet oxygen, thereby causing oxidant damage to mitochondria and then the apoptosis of the cells. Analysis via 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyltetrazolium bromide (MTT) assays indicate that the novel PDT system exhibits enhanced cytotoxicity toward cancer cells. This study may offer a new strategy for designing PDT systems with high efficacy and low side effects. PMID:27774388

Multifunctional Surface-Enhanced Raman Spectroscopy-Detectable Silver Nanoparticles Combined Photodynamic Therapy and pH-Triggered Chemotherapy.

PubMed

Srinivasan, Supriya; Bhardwaj, Vinay; Nagasetti, Abhignyan; Fernandez-Fernandez, Alicia; McGoron, Anthony J

2016-12-01

This research paper reports the development of a multifunctional anti-cancer prodrug system based on silver nanoparticles. This prodrug system is composed of 70-nm sized nanoparticles and features photodynamic therapeutic properties and active, pH-triggered drug release. The silver nanoparticles are decorated with a folic acid (FA) targeting ligand via an amide bond, and also conjugated to the chemotherapeutic drug doxorubicin (DOX) via an acid-cleavable hydrazone bond. Both FA and DOX are attached to the silver nanoparticles through a polyethylene glycol (PEG) spacer. This prodrug system can preferentially enter cells that over-express folic acid receptors, with subsequent intracellular drug release triggered by reduced intracellular pH. Moreover, the silver nanoparticle carrier system exhibits photodynamic therapeutic (PDT) activity, so that the cell viability of cancer cells that overexpress folate receptors can be further reduced upon light irradiation. The dual effects of pH-triggered drug release and PDT increase the therapeutic efficacy of this system. The multifunctional nanoparticles can be probed intracellularly through Surface-Enhanced Raman Spectroscopy (SERS) and fluorescence spectroscopy. The current report explores the applicability of this multifunctional silver nanoparticle-based system for cancer theranostics.

Fluorescence intensity and bright spot analyses using a confocal microscope for photodynamic diagnosis of brain tumors.

PubMed

Yoneyama, Takeshi; Watanabe, Tetsuyo; Kagawa, Hiroyuki; Hayashi, Yutaka; Nakada, Mitsutoshi

2017-03-01

In photodynamic diagnosis using 5-aminolevulinic acid (5-ALA), discrimination between the tumor and normal tissue is very important for a precise resection. However, it is difficult to distinguish between infiltrating tumor and normal regions in the boundary area. In this study, fluorescent intensity and bright spot analyses using a confocal microscope is proposed for the precise discrimination between infiltrating tumor and normal regions. From the 5-ALA-resected brain tumor tissue, the red fluorescent and marginal regions were sliced for observation under a confocal microscope. Hematoxylin and eosin (H&E) staining were performed on serial slices of the same tissue. According to the pathological inspection of the H&E slides, the tumor and infiltrating and normal regions on confocal microscopy images were investigated. From the fluorescent intensity of the image pixels, a histogram of pixel number with the same fluorescent intensity was obtained. The fluorescent bright spot sizes and total number were compared between the marginal and normal regions. The fluorescence intensity distribution and average intensity in the tumor were different from those in the normal region. The probability of a difference from the dark enhanced the difference between the tumor and the normal region. The bright spot size and number in the infiltrating tumor were different from those in the normal region. Fluorescence intensity analysis is useful to distinguish a tumor region, and a bright spot analysis is useful to distinguish between infiltrating tumor and normal regions. These methods will be important for the precise resection or photodynamic therapy of brain tumors. Copyright © 2016 Elsevier B.V. All rights reserved.

[Retrospective, descriptive, observational study of treatment of multiple actinic keratoses with topical methyl aminolevulinate and red light: results in clinical practice and correlation with fluorescence imaging].

PubMed

Fernández-Guarino, M; Harto, A; Sánchez-Ronco, M; Pérez-García, B; Marquet, A; Jaén, P

2008-12-01

Actinic keratosis (AK) is one of the most common skin diseases seen in clinical practice. In the last 5 years, several studies assessing the efficacy of photodynamic therapy in the treatment of multiple AKs have been published. We aimed to assess the clinical outcomes of photodynamic therapy in patients with multiple AKs and the correlation of those outcomes with fluorescence imaging. In this retrospective, descriptive, observational study of 57 patients treated in our hospital with photodynamic therapy for multiple AKs, we recorded age, sex, and lesion site (face, scalp, and dorsum of the hands). All patients were treated in the same way: methyl aminolevulinic acid (Metvix) was applied for 3 hours and the skin then irradiated with red light at 630 nm, 37 J/cm(2), for 7.5 minutes (Aktilite). The response, remission duration, tolerance, number of sessions, and fluorescence images were recorded by site. The chi(2) test was used to assess between-site differences and the correlation between fluorescence imaging and clinical response. The greatest improvements were obtained for facial lesions; these required fewer sessions and remission lasted longer than lesions at other sites. The treatment was best tolerated on the dorsum of the hands. The fluorescence area and the reduction in intensity on applying treatment were found to be strongly and significantly correlated with the extent of clinical response. Overall, the outcomes of treatment of multiple AKs with photodynamic therapy are better for the face than for the scalp and dorsum of the hands. Fluorescence imaging may be an effective tool for predicting response to treatment.

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.

Photodynamic therapy in Argentina.

PubMed

Casas, Adriana; Batlle, Alcira

2006-12-01

The use of endogenous Protoporphyrin IX generated through the heme biosynthetic pathway after administration of 5-aminolevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). In Buenos Aires, Argentina, the Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), reported for the first time, in 1975, porphyrin synthesis from ALA in highly dividing plant tissues. Increased porphyrin synthesis in tumours as well as cell photosensitisation was reported soon after. Our group is also interested in studying the use of new synthetic lipophilic derivatives of ALA as well as ALA delivery in liposomes. We have elucidated the mechanism of ALA transport in mammalian and yeast cells. The interactions between ALA-PDT and nitric oxide were investigated in three murine adenocarcinoma cell lines. In the National University of Río Cuarto, Córdoba, a group is devoted to the synthesis of new porphyrin-derived photosensitisers to study their effects on photoinactivation of bacterial and mammalian cells death by PDT. At the Centre of Electron Microscopy of the Cordoba National University, a prototype of a 630nm noncoherent light source was designed and constructed. Cost of the light source and scarce knowledge of the benefits of PDT by physicians limit the spread of the treatment throughout the country.

Comparative analysis of the effects of CO2 fractional laser and sonophoresis on human skin penetration with 5-aminolevulinic acid.

PubMed

Choi, J H; Shin, E J; Jeong, K H; Shin, M K

2017-11-01

Successful delivery of a photosensitizer into the skin is an important factor for effective photodynamic therapy (PDT). The effective method to increase drug penetration within short incubation time overcoming skin barrier have been investigated. This study was performed to analyze and compare the effectiveness of ablative fractional laser (FXL) pretreatment and/or sonophoresis for enhancing the penetration of 5-aminolevulinic acid (ALA) into human skin in vivo. Twenty-four identical 1 × 1 cm 2 treatment areas were mapped on the backs of ten healthy male subjects. Each area received FXL pretreatment and/or sonophoresis with different energy settings and ALA incubation times. After treatments, porphyrin fluorescence reflecting the ALA penetration were measured. Application of ablative CO 2 FXL pretreatment resulted to higher fluorescence intensities than the non-treatment group. Incubation times were positively correlated with the increments of ALA penetration. However, increasing pulse energy or combining with sonophoresis did not show additional positive effects on ALA penetration. Ablative CO 2 FXL pretreatment effectively facilitated ALA penetration in human skin in vivo. Ablative CO 2 FXL alone without sonophoresis setting pulse energy of 10 and 20 mJ with more than 60 min of ALA incubation time could be an ideal setting for ALA penetration.

Enhanced photodynamic activity of hypericin by penetration enhancer N-methyl pyrrolidone formulations in the chick chorioallantoic membrane model.

PubMed

Saw, Constance Lay Lay; Heng, Paul Wan Sia; Chin, William Wei Lim; Soo, Khee Chee; Olivo, Malini

2006-07-08

Hypericin (HY) was examined for photodynamic therapy (PDT)-induced vascular damage using the chick chorioallantoic membrane (CAM) model. Clinically, plasma protein was used to solubilize HY. Upon binding to albumin, free HY available to be transported through the membrane may be limited. Hence, formulations containing a biocompatible solvent, N-Methyl pyrrolidone (NMP), have the potential to enhance HY delivery into solid tumors. At suitable concentrations, NMP and/or light irradiation did not produce antivascular damage. Hypericin-PDT effects showed to be HY and NMP concentrations-dependent. These findings indicate that NMP is a promising solvent and penetration enhancer for HY-PDT clinical applications.

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.

Tumor-Triggered Geometrical Shape Switch of Chimeric Peptide for Enhanced in Vivo Tumor Internalization and Photodynamic Therapy.

PubMed

Han, Kai; Zhang, Jin; Zhang, Weiyun; Wang, Shibo; Xu, Luming; Zhang, Chi; Zhang, Xianzheng; Han, Heyou

2017-03-28

Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this article, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy, and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.

Evaluation of a water-soluble bioadhesive patch for photodynamic therapy of vulval lesions.

PubMed

McCarron, Paul A; Donnelly, Ryan F; Zawislak, Agnieszka; Woolfson, A David; Price, John H; McClelland, Raymond

2005-04-11

An innovative bioadhesive patch intended primarily as a vulval drug delivery system and, specifically, as a means to deliver photosensitisers, or their prodrugs, for photodynamic purposes is described. The patch was formulated with a copolymer of methyl vinyl ether and maleic anhydride (PMVE/MA) as a bioadhesive matrix and poly(vinyl chloride) as a drug-impervious backing layer. Adhesive strength to neonate porcine skin, as a model substrate, was evaluated using peel and tensile testing measurements. Acceptabilities of non-drug loaded patches were appraised using human volunteers and visual-analogue scoring devices. An optimal formulation, with water uptake and peel strengths appropriate for vulval drug delivery, was cast from a 20% (w/w) PMVE/MA solution and adhered with a strength of approximately 1.7 Ncm(-2). Patient evaluation demonstrated comfort and firm attachment for up to 4h in mobile patients. Aminolevulinic acid, a commonly used photosensitiser, was formulated into the candidate formulation and applied to vulval intraepithelial neoplastic lesions. Fluorescence under ultraviolet illumination revealed protoporphyrin synthesis. The patch achieves the extended application times obligatory in topical photodynamic therapy of vulval lesions, thereby contributing to potential methods for the eradication of neoplastic lesions in the lower female reproductive tract.

Photodynamic Therapy Effectively Treats Actinic Keratoses Without Pre-Illumination Incubation Time.

PubMed

Gandy, Jessica; Labadie, Brian; Bierman, Dina; Zachary, Christopher

2017-03-01

BACKGROUND: Actinic keratoses (AKs) are dysplastic lesions of the epidermis that have the potential to progress to non-melanoma skin cancers (NMSC). Traditional photodynamic therapy (PDT) requires a pre-illumination incubation time, which adds to overall in-office time and has been linked to pain. Our group has found a novel protocol to effectively treat AKs with PDT that eliminates the pre-illumination incubation period and uses 2 back-to-back cycles of 16 minute 40 seconds.

METHODS: The patient was prepped with soapy water and isopropyl alcohol, and thick AKs were descaled with a curette. Next, 5-aminolevulinic acid (ALA) was applied to the treatment areas and the patient was immediately placed under the blue light for 33 minutes and 20 seconds (two cycles of 16m/40s).

RESULTS: During therapy, the patient reported no pain. At one week, treated areas revealed a good reaction. The procedure was repeated at one month to treat residual AKs. At a 4-month follow-up, the patient's face and scalp showed near clearance of any AKs.

CONCLUSION: During PDT, the photosensitizer aminolevulinic acid (ALA), or in Europe methyl aminolevulinate (MAL), is utilized as a synthetic precursor that preferentially accumulates in dysplastic cells. The precursor then converts to PpIX via the heme pathway and causes apoptosis of the cells when excited, most commonly by either blue-violet (400-430 nm) or red (630-635 nm) light. Shorter incubation times are associated with reduced pain because less PpIX will have accumulated in the treated tissue by the start of the exposure to the light. The doubling of the light exposure time allows comparable levels of the photosensitizing molecule to accumulate and be activated so as to produce an equivalent reaction. The associated reduction in pain along with a more convenient treatment schedule makes this PDT protocol more tolerable and convenient to some patients.

J Drugs Dermatol. 2017;16(3):275-278.

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

NASA Astrophysics Data System (ADS)

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.

The utility of 5-aminolevulinic acid-mediated photodynamic diagnosis in the detection of intraoperative bile leakage.

PubMed

Inoue, Yoshihiro; Imai, Yoshiro; Fujii, Kensuke; Hirokawa, Fumitoshi; Hayashi, Michihiro; Uchiyama, Kazuhisa

2017-06-01

The purpose of this retrospective study was to evaluate the utility of the new intraoperative bile leakage test as a preventive measure of postoperative bile leakage. 737 patients were retrospectively analyzed with respect to the management of intra- and post-operative bile leakage. Nine (8.3%) of 109 patients evaluated using conventional white light fluorescent imaging were recognized as having intra-operative bile leakage. However, performance of 5-aminolevulinic acid (5-ALA)-mediated PDD detected bile leakage intraoperatively not only in these 9 patients, but also in an additional 6 patients, such that 'red fluorescence' at the cut surface of the liver, was visualized in a total of 15 patients. The postoperative courses of most patients were uneventful, and postoperative bile leakages occurred in only one (0.9%) patient. 5-ALA fluorescence imaging may be needed to prevent postoperative bile leakage in patients at high risk for this surgical complication after hepatic resection. Copyright © 2016 Elsevier Inc. All rights reserved.

Cationic Phosphorus Dendrimer Enhances Photodynamic Activity of Rose Bengal against Basal Cell Carcinoma Cell Lines.

PubMed

Dabrzalska, Monika; Janaszewska, Anna; Zablocka, Maria; Mignani, Serge; Majoral, Jean Pierre; Klajnert-Maculewicz, Barbara

2017-05-01

In the last couple of decades, photodynamic therapy emerged as a useful tool in the treatment of basal cell carcinoma. However, it still meets limitations due to unfavorable properties of photosensitizers such as poor solubility or lack of selectivity. Dendrimers, polymers widely studied in biomedical field, may play a role as photosensitizer carriers and improve the efficacy of photodynamic treatment. Here, we describe the evaluation of an electrostatic complex of cationic phosphorus dendrimer and rose bengal in such aspects as singlet oxygen production, cellular uptake, and phototoxicity against three basal cell carcinoma cell lines. Rose bengal-cationic dendrimer complex in molar ratio 5:1 was compared to free rose bengal. Obtained results showed that the singlet oxygen production in aqueous medium was significantly higher for the complex than for free rose bengal. The cellular uptake of the complex was 2-7-fold higher compared to a free photosensitizer. Importantly, rose bengal, rose bengal-dendrimer complex, and dendrimer itself showed no dark toxicity against all three cell lines. Moreover, we observed that phototoxicity of the complex was remarkably enhanced presumably due to high cellular uptake. On the basis of the obtained results, we conclude that rose bengal-cationic dendrimer complex has a potential in photodynamic treatment of basal cell carcinoma.

5-Aminolevulinic acid-based photochemical internalization of the immunotoxin MOC31-gelonin generates synergistic cytotoxic effects in vitro.

PubMed

Selbo, P K; Kaalhus, O; Sivam, G; Berg, K

2001-08-01

Photochemical internalization (PCI) is a novel method for the endosomal or lysosomal release of membrane-impermeable molecules into the cytosol of target cells. This novel technology is based on the photodynamically induced rupture of endocytic vesicles preloaded with molecules of therapeutic interest. PCI of the ribosome-inactivating plant toxin gelonin and the immunotoxin monoclonal antibody 31 (MOC31) gelonin has been performed previously by the use of the endocytic vesicle-localizing photosensitizers TPPS2a and AIPcS2a and light, demonstrating synergistic toxicity against the more than 20 different cell lines tested, most of them of neoplastic origin. In this study we demonstrate that 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) is also capable of inducing PCI of MOC31-gelonin in the human colon adenocarcinoma cell line WiDr. The cells were incubated with 1 mM 5-ALA for up to 8 h in serum-free medium and from 24 to 96 h in serum-containing medium. Fluorescence microscopical studies indicate a partial plasma membrane localization of PpIX when 5-ALA was applied under serum-free conditions. This plasma membrane localization was not seen when 5-ALA was given in the presence of serum. There was a granular component of the PpIX localization in addition to a diffuse cytoplasmic localization. The granular component resembled the localization of the fluorescent dye conjugate Alexa-gelonin and the lysosomal localizing dye acridine orange. Our present results provide evidence for an endocytic vesicle-associated fraction of PpIX after 5-ALA incubation of the WiDr cells. We demonstrate that PCI, by combining 5-ALA, MOC31-gelonin and light, induces a synergistic cytotoxic effect against the WiDr cells.

Transferrin-Modified Nanoparticles for Photodynamic Therapy Enhance the Antitumor Efficacy of Hypocrellin A

PubMed Central

Lin, Xi; Yan, Shu-Zhen; Qi, Shan-Shan; Xu, Qiao; Han, Shuang-Shuang; Guo, Ling-Yuan; Zhao, Ning; Chen, Shuang-Lin; Yu, Shu-Qin

2017-01-01

Photodynamic therapy (PDT) has emerged as a potent novel therapeutic modality that induces cell death through light-induced activation of photosensitizer. But some photosensitizers have characteristics of poor water-solubility and non-specific tissue distribution. These characteristics become main obstacles of PDT. In this paper, we synthesized a targeting drug delivery system (TDDS) to improve the water-solubility of photosensitizer and enhance the ability of targeted TFR positive tumor cells. TDDS is a transferrin-modified Poly(D,L-Lactide-co-glycolide (PLGA) and carboxymethyl chitosan (CMC) nanoparticle loaded with a photosensitizer hypocrellin A (HA), named TF-HA-CMC-PLGA NPs. Morphology, size distribution, Fourier transform infrared (FT-IR) spectra, encapsulation efficiency, and loading capacity of TF-HA-CMC-PLGA NPs were characterized. In vitro TF-HA-CMC-PLGA NPs presented weak dark cytotoxicity and significant photo-cytotoxicity with strong reactive oxygen species (ROS) generation and apoptotic cancer cell death. In vivo photodynamic antitumor efficacy of TF-HA-CMC-PLGA NPs was investigated with an A549 (TFR positive) tumor-bearing model in male athymic nude mice. TF-HA-CMC-PLGA NPs caused tumor delay with a remarkable tumor inhibition rate of 63% for 15 days. Extensive cell apoptosis in tumor tissue and slight side effects in normal organs were observed. The results indicated that TDDS has great potential to enhance PDT therapeutic efficacy. PMID:29209206

Novel theranostic zinc phthalocyanine-phospholipid complex self-assembled nanoparticles for imaging-guided targeted photodynamic treatment with controllable ROS production and shape-assisted enhanced cellular uptake.

PubMed

Ma, Jinyuan; Li, Yang; Liu, Guihua; Li, Ai; Chen, Yilin; Zhou, Xinyi; Chen, Dengyue; Hou, Zhenqing; Zhu, Xuan

2018-02-01

The novel drug delivery system based on self-assembly of zinc phthalocyanine-soybean phosphatidylcholine (ZnPc-SPC) complex was developed by a co-solvent method followed by a nanoprecipitaion technique. DSPE-PEG-methotrexate (DSPE-PEG-MTX) was introduced on the surface of ZnPc-SPC self-assembled nanoparticles (ZS) to endow them with folate receptor-targeting property. NMR, XRD, FTIR, and UV-vis-NIR analysis demonstrated the weak molecular interaction between ZnPc and SPC. The ZS functionalized with DSPE-PEG-MTX (ZSPM) was successfully constructed with an average particle size of ∼170nm, a narrow size distribution, and could remain physiologically stable for at least 7days. In vitro cellular uptake and cytotoxicity studies demonstrated that ZSPM exhibited stronger cellular uptake efficacy and photodynamic cytotoxicity against HeLa and MCF-7 cells than ZS functionalized with DSPE-mPEG (ZSP) and free ZnPc. More importantly, ZSPM showed the enhanced accumulation effect at the tumor region compared with ZSP by the active-plus-passive targeting via enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis. Furthermore, in vivo antitumor effect and histological analysis demonstrated the superior tumor growth inhibition effect of ZSPM. In addition, the needle-shape ZSP (ZSPN) exhibited better in vitro cellular uptake and in vivo tumor accumulation compared with ZSP due to the shape-assisted effect. Moreover, the interesting off-on switch effect of reactive oxygen species (ROS) production of ZnPc-SPC complex-based nanoparticles was discovered to achieve photodynamic treatment in a controllable way. These findings suggested that the ZnPc-SPC complex-based self-assembled nanoparticles could serve as a promising and effective formulation to achieve tumor-targeting fluorescence imaging and enhanced photodynamic treatment. Copyright © 2017. Published by Elsevier B.V.

Topical hexaminolevulinate photodynamic therapy for the treatment of persistent human papilloma virus infections and cervical intraepithelial neoplasia.

PubMed

Hillemanns, Peter; Einstein, Mark H; Iversen, Ole Erik

2015-02-01

Current treatments for high-grade cervical intraepithelial neoplasia (CIN2/3) are mainly excisional procedures, which are associated with significant side effects and pose risks for future pregnancies. An effective and safe therapy is needed to reduce the requirement for surgical interventions in women of reproductive age. This review looks at the pharmacokinetic and clinical data for topical hexaminolevulinate (HAL) photodynamic therapy (PDT), which is currently entering late phase clinical trials for high-grade CIN. The authors include published studies in patients and volunteers but laboratory and animal studies have been excluded as have studies on other porphyrins such as Photofrin, 5-aminolevulinic acid, methyl aminolevulinate and studies reporting other clinical applications for HAL. Topical HAL PDT has potential as a non-surgical tissue-preserving treatment for CIN and persistent oncogenic human papilloma virus infections. HAL PDT selectively treats the entire epithelial sheet, without the tissue destruction seen in excisional procedures. The authors believe that this treatment could replace surgery in a large proportion of patients. It would be of particular value to the high percentage of women who are interested in future child-bearing. If the treatment is approved, it is very likely that physicians will want to use this treatment, as many patients will be keen to consider a non-surgical option.

Ambulant photodynamic therapy of superficial malignomas with 5-ALA in combination with folic acid and use of noncoherent light.

PubMed

Jindra, R H; Kubin, A; Kolbabek, H; Alth, G; Dobrowsky, W

1999-01-01

This study reports our first results of ambulant photodynamic treatment with 5-aminolevulinic acid (5-ALA) in combination with folic acid and subsequent illumination with a noncoherent light source. The compound was topically applied to avoid total body skin sensitivity which occurs in the case of systemic administration. If no therapeutic response could be proved, we added folic acid to 5-ALA for a further treatment attempt. Illumination was performed by broad band red thermic light to also excitate reaction products with absorption bands located near to that of the sensitizer. As a result, we observed a response in all cases, however, in some cases only after the addition of folic acid.

Studying the effect of photodynamic therapy (PDT) to enhance healing of femur fractures using polarimetric second-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Golaraei, Ahmad; Raja, Vaishnavi; Akens, Margarete K.; Wilson, Brian C.; Barzda, Virginijus

2017-07-01

Linear polarization-in, polarization-out second-harmonic generation microscopy was used to study the effect of Photodynamic therapy treatment on enhancing the healing of femur fracture by investigating the ultrastructure of collagen as a major component of bone matrix.

Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models.

PubMed

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

2015-03-02

Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6-fold in vivo . In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p < 0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care.

Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models

PubMed Central

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

2015-01-01

Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6-fold in vivo. In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p < 0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care. PMID:25983370

Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models

NASA Astrophysics Data System (ADS)

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

2015-03-01

Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6- fold in vivo. In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p <0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care.

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.

Photodynamic therapy in the management of actinic keratosis: Retrospective evaluation of outcome.

PubMed

Jerjes, Waseem; Hamdoon, Zaid; Abdulkareem, Ali A; Hopper, Colin

2017-03-01

Photodynamic therapy (PDT) is a minimally invasive intervention used in the management of tissue disorders. In this retrospective study, a total of 62 patients with actinic keratosis (AKs) were treated with surface illumination PDT. Comparisons with the clinical features, rate of recurrence as well as malignant transformation and overall outcome were made. The medical records of 62 consecutive patients who presented with suspicious skin lesions and diagnosed with AKs were examined. These patients with 178 AKs lesions were treated with surface illumination methyl aminolevulinate-photodynamic therapy (MAL-PDT). The 16% strength cream (MAL) was applied topically 3h prior to tissue illumination. A single-channel 628nm diode laser was used for illumination and light was delivered at 100J/cm 2 per site. These patients were followed-up for a mean of 7.4 years. Eight recurrences were reported after the first round of MAL-PDT, and two recurrences after the second round. Malignant transformation to squamous cell carcinoma (SCC) was noted in 2 patients only. The 3-year outcome resulted in 60 patients with complete response (CR), and this was maintained at the final outcome (last clinic review). Assessment of lesional outcome vs. response showed that 175/178 treated lesions had complete response (CR) at 3-year follow-up, which increased to 176/178 lesions at the last clinic follow-up. MAL-PDT offers an effective treatment for AKs lesions with excellent cosmetic outcome. Copyright © 2016 Elsevier B.V. All rights reserved.

Decreased metastatic phenotype in cells resistant to Aminolevulinic acid-Photodynamic therapy

PubMed Central

Casas, Adriana; Di Venosa, Gabriela; Vanzulli, Silvia; Perotti, Christian; Mamome, Leandro; Rodriguez, Lorena; Simian, Marina; Juarranz, Angeles; Pontiggia, Osvaldo; Hasan, Tayyaba; Batlle, Alcira

2008-01-01

Photodynamic therapy (PDT) is a novel cancer treatment utilising a photosensitiser, visible light and oxygen. PDT often leaves a significant number of surviving tumour cells. In a previous work, we isolated and studied two PDT resistant clones derived from the mammary adenocarcinoma LM3 line (Int. J. Oncol. 29 (2006) 397–405). The isolated Clon 4 and Clon 8 exhibited a more fibroblastic, dendritic pattern and were larger than the parentals. In the present work we studied the metastatic potential of the two clones in comparison with LM3. We found that 100 % of LM3 invaded Matrigel, whereas only 19 ± 6 % and 24 ± 7 % of Clon 4 and Clon 8 cells invaded. In addition, 100% of LM3 cells migrated towards a chemotactic stimulus whereas 38 ± 8 % and 73 ± 10 % of Clones 4 and 8 respectively were able to migrate. In vivo, 100% of the LM3 injected mice developed spontaneous lung metastasis, whereas none of the Clon 8 did, and only one of the mice injected with Clon 4 did. No differences were found in the proteolytic enzyme profiles among the cells. Anchorage-dependent adhesion was also impaired in vivo in the resistant clones, evidenced by the lower tumour take, latency time and growth rates, although both clones showed in vitro higher binding to collagen I without overexpression of β1 integrin. This is the first work where the metastatic potential of cells surviving to PDT has been studied. PDT strongly affects the invasive phenotype of these cells, probably related to a higher binding to collagen. These findings may be crucial for the outcome of ALA-PDT of metastatic tumours, although further studies are needed to extrapolate the results to the clinic employing another photosensitisers and cell types. PMID:18662847

Short incubation fractional CO2 laser-assisted photodynamic therapy vs. conventional photodynamic therapy in field-cancerized skin: 12-month follow-up results of a randomized intraindividual comparison study.

PubMed

Vrani, F; Sotiriou, E; Lazaridou, E; Vakirlis, E; Sideris, N; Kirmanidou, E; Apalla, Z; Lallas, A; Ioannides, D

2018-06-04

Topical methyl aminolevulinate photodynamic therapy (MAL-PDT) with 3 h incubation is recommended as a field directed treatment. Skin pretreatment with ablative CO 2 fractional laser (AFXL) prior to MAL-PDT enhances drug penetration and could minimize incubation time. To evaluate and compare the safety and the preventive effect in the development of new non-melanocytic skin cancers (NMSCs) of AFXL-assisted MAL-PDT with 1-h incubation with that of conventional MAL-PDT in patients with clinical and histological signs of field cancerization. Forty-two patients with two mirror cancerized areas of face or scalp were randomized to field treatment with 1-h incubation AFXL-assisted PDT or conventional PDT (CPDT). All patients underwent two treatment sessions 1 week apart. Irradiation was performed using a red light-emitting diode lamp at 37 J/cm 2 . Patients were followed up at 3, 6, 9 and 12 months for the evaluation of development of new NMSCs lesions. All patients completed the study. There was no statistically significant difference with respect to the total number of new actinic keratoses at any point of follow-up as well as to the mean time of occurrence of new lesions between treatment fields. Both treatment regimens were safe and well tolerated. Ablative CO 2 fractional laser pretreatment may be considered as an option for reducing photosensitizer occlusion time while providing the same preventative efficacy as CPDT in patients with field-cancerized skin. © 2018 European Academy of Dermatology and Venereology.

Development of Smart Phthalocyanine-based Photosensitizers for Photodynamic Therapy

NASA Astrophysics Data System (ADS)

Chow, Yun Sang

Phthalocyanines are versatile functional dyes that have shown great potential in cancer theranostics, especially in photodynamic therapy (PDT). This research work aims to develop "smart" phthalocyanine-based photosensitizers for targeted PDT. This thesis describes the synthesis, spectroscopic characterization, photophysical properties, and in vitro photodynamic activities of several series of carefully designed phthalocyanine-based photosensitizers. Chapter 1 presents an overview of PDT, including its historical development, photophysical mechanisms, and biological mechanisms. Various classes of photosensitizers are introduced with emphasis putting on phthalocyanines, which exhibit ideal characteristics of photosensitizers for PDT. In recent years, several approaches have been used to develop photosensitizers with higher tumor selectivity and minimal skin photosensitivity after PDT. Activatable photosensitizers can provide a "turn on" mechanism to offer an additional control of the specificity of treatment. Photosensitizers can also work cooperatively with the tumor-targeting groups or anticancer drugs so as to achieve targeted or dual therapy, which can enhance the efficacy of PDT. The novel approaches mentioned above have been widely used and combined to form multi-functional photosensitizing agents. These novel concepts and development of PDT are discussed and illustrated with relevant examples at the end of this chapter. To minimize the prolonged skin photosensitivity, photosensitizers that can only be activated by tumor-associated stimuli have been developed. Due to the abnormal metabolism in tumor tissues, their surface usually exhibits a lower pH compared to that of the normal tissues. Also, the pH difference between the intracellular and the physiological environment provides a pH-activation mechanism. Chapter 2 presents the synthesis and spectroscopic characterization of a pH-responsive zinc(II) phthalocyanine tetramer, in which the phthalocyanine units

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.

Pharmaceutical micelles featured with singlet oxygen-responsive cargo release and mitochondrial targeting for enhanced photodynamic therapy.

PubMed

Zhang, Xin; Yan, Qi; Mulatihan, Di Naer; Zhu, Jundong; Fan, Aiping; Wang, Zheng; Zhao, Yanjun

2018-06-22

The efficacy of nanoparticulate photodynamic therapy is often compromised by the short life time and limited diffusion radius of singlet oxygen as well as uncontrolled intracellular distribution of photosensitizer. It was hypothesized that rapid photosensitizer release upon nanoparticle internalization and its preferred accumulation in mitochondria would address the above problems. Hence, the aim of this study was to engineer a multifunctional micellar nanosystem featured with singlet oxygen-responsive cargo release and mitochondria-targeting. An imidazole-bearing amphiphilic copolymer was employed as the micelle building block to encapsulate triphenylphosphonium-pyropheophorbide a (TPP-PPa) conjugate or PPa. Upon laser irradiation, the singlet oxygen produced by TPP-PPa/PPa oxidized the imidazole moiety to produce hydrophilic urea, leading to micelle disassembly and rapid cargo release. The co-localization analysis showed that the TPP moiety significantly enhanced the photosensitizer uptake by mitochondria, improved mitochondria depolarization upon irradiation, and hence boosted the cytotoxicity in 4T1 cells. The targeting strategy also dramatically reduced the intracellular ATP concentration as a consequence of mitochondria injury. The mitochondria damage was accompanied with the activation of the apoptosis signals (caspase 3 and caspase 9), whose level was directly correlated to the apoptosis extent. The current work provides a facile and robust means to enhance the efficacy of photodynamic therapy.

Pharmaceutical micelles featured with singlet oxygen-responsive cargo release and mitochondrial targeting for enhanced photodynamic therapy

NASA Astrophysics Data System (ADS)

Zhang, Xin; Yan, Qi; Naer Mulatihan, Di; Zhu, Jundong; Fan, Aiping; Wang, Zheng; Zhao, Yanjun

2018-06-01

The efficacy of nanoparticulate photodynamic therapy is often compromised by the short life time and limited diffusion radius of singlet oxygen as well as uncontrolled intracellular distribution of photosensitizer. It was hypothesized that rapid photosensitizer release upon nanoparticle internalization and its preferred accumulation in mitochondria would address the above problems. Hence, the aim of this study was to engineer a multifunctional micellar nanosystem featured with singlet oxygen-responsive cargo release and mitochondria-targeting. An imidazole-bearing amphiphilic copolymer was employed as the micelle building block to encapsulate triphenylphosphonium-pyropheophorbide a (TPP-PPa) conjugate or PPa. Upon laser irradiation, the singlet oxygen produced by TPP-PPa/PPa oxidized the imidazole moiety to produce hydrophilic urea, leading to micelle disassembly and rapid cargo release. The co-localization analysis showed that the TPP moiety significantly enhanced the photosensitizer uptake by mitochondria, improved mitochondria depolarization upon irradiation, and hence boosted the cytotoxicity in 4T1 cells. The targeting strategy also dramatically reduced the intracellular ATP concentration as a consequence of mitochondria injury. The mitochondria damage was accompanied with the activation of the apoptosis signals (caspase 3 and caspase 9), whose level was directly correlated to the apoptosis extent. The current work provides a facile and robust means to enhance the efficacy of photodynamic therapy.

Pharmacokinetics of endogenous porphyrins induced by 5-aminolevulinic acid as observed by means of laser-induced fluorescence from several organs of tumor-bearing mice

NASA Astrophysics Data System (ADS)

Sroka, Ronald; Baumgartner, Reinhold; Beyer, Wolfgang; Gossner, Liebwin; Sassy, T.; Stocker, Susanne

1995-04-01

Photodynamic therapy (PDT) and photodynamic diagnosis (PDD) add support to efficient treatment modalities of superficial and early stage cancer. Recently 5-aminolevulinic acid (5-ALA), a precursor of hemoglobin in the hem biosynthetic pathway, was used to stimulate endogenous porphyrin production. The time dependency of 5-ALA induced porphyrin fluorescence has been investigated on several normal tissues as well as on a tumor in an in-vivo tumor model (human gastrointestinal adenocarcinoma Grade II, UICC IIa). 5-ALA has been administered intravenously at a concentration of 50 mg/(kg bw). With respect to a certain time schedule the animals were sacrificed and 12 different organs as well as the tumor were removed. Using laser-induced fluorescence techniques the emission spectra in the range of (lambda) equals (550-750) nm were detected from the tissues after excitation with light of the wavelength (lambda) equals (411 +/- 4) nm. For quantitative evaluation the integral fluorescence intensity at (lambda) equals (635 +/- 2) nm of the porphyrin specific spectra has been determined. All tissues showed porphyrin fluorescence, while brightest fluorescence has been detected from the tumor. With respect to the other tissues the relative tumor selectivity showed a maximum ratio at 406 h post injection. The kinetics of the porphyrin fluorescence intensity of the organs follow different time dependencies. Simple mathematical pharmacokinetic models are developed and discussed.

Molecular beacon-based photodynamic therapy

NASA Astrophysics Data System (ADS)

Chen, Juan; Stefflova, Klara; Kim, Soungkyoo; Li, Hui; Marotta, Diane; Chance, Britton; Glickson, Jerry D.; Zheng, Gang

2005-01-01

A new concept for photodynamic therapy (PDT) has been developed based on incorporating a photosensitizer (PS) and a singlet oxygen (1O2) quenching/scavenging molecule (Q) onto a disease-targeting carrier, such that the PS becomes activatable by light only when targeting has occurred. This has the potential to give very high disease specificity in PDT treatment. The first model compound designed using this concept was synthesized containing a pyropheophorbide as the PS and a carotenoid as the 1O2 quencher. These were kept in close proximity by the self-folding of a caspase-3 specific peptide sequence. Upon caspase-3-induced cleavage, the 1O2 production increase has been validated by direct 1O2 luminescence and lifetime measurements, providing proof-of-concept of this 'PDT beacon.'

Photodynamic therapy for cancer

MedlinePlus

... Photoradiation therapy; 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 ...

Fluorination of phthalocyanine substituents: Improved photoproperties and enhanced photodynamic efficacy after optimal micellar formulations.

PubMed

Pucelik, Barbara; Gürol, Ilke; Ahsen, Vefa; Dumoulin, Fabienne; Dąbrowski, Janusz M

2016-11-29

A fluorinated phthalocyanine and its non-fluorinated analogue were selected to evaluate the potential enhancement of fluorination on photophysical, photochemical and redox properties as well as on biological activity in cellular and animal models. Due to the pharmacological relevance, the affinity of these phthalocyanines towards biological membranes (logP ow ) as well as their primary interaction with human serum albumin (HSA) or low-density lipoprotein (LDL) were determined. Water-dispersible drug formulation of phthalocyanines via Pluronic ® -based triblock copolymer micelles was prepared to avoid self-aggregation effects and to improve their delivery. The obtained results demonstrate that phthalocyanines incorporation into tunable-polymeric micelles significantly enhanced their cellular uptake and their photocytotoxicity. The improved biodistribution and photodynamic efficacy of the phthalocyanines-triblock copolymer conjugates was also confirmed in vivo in CT26 bearing BALB/c mice. PDT with both compounds led to tumor growth inhibition in all treated animals. Fluorinated phthalocyanine 2 turned out to be the most effective anticancer agent as the tumors of 20% of mice treated regressed completely and did not appear for over one year after treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Combined photothermal and photodynamic therapy delivered by PEGylated MoS2 nanosheets

NASA Astrophysics Data System (ADS)

Liu, Teng; Wang, Chao; Cui, Wei; Gong, Hua; Liang, Chao; Shi, Xiaoze; Li, Zhiwei; Sun, Baoquan; Liu, Zhuang

2014-09-01

Single- or few-layered transitional metal dichalcogenides, as a new genus of two-dimensional nanomaterials, have attracted tremendous attention in recent years, owing to their various intriguing properties. In this study, chemically exfoliated MoS2 nanosheets are modified with lipoic acid-terminated polyethylene glycol (LA-PEG), obtaining PEGylated MoS2 (MoS2-PEG) with high stability in physiological solutions and no obvious toxicity. Taking advantage of its ultra-high surface area, the obtained MoS2-PEG is able to load a photodynamic agent, chlorin e6 (Ce6), by physical adsorption. In vitro experiments reveal that Ce6 after being loaded on MoS2-PEG shows remarkably increased cellular uptake and thus significantly enhanced photodynamic therapeutic efficiency. Utilizing the strong, near-infrared (NIR) absorbance of the MoS2 nanosheets, we further demonstrate photothermally enhanced photodynamic therapy using Ce6-loaded MoS2-PEG for synergistic cancer killing, in both in vitro cellular and in vivo animal experiments. Our study presents a new type of multifunctional nanocarrier for the delivery of photodynamic therapy, which, if combined with photothermal therapy, appears to be an effective therapeutic approach for cancer treatment.Single- or few-layered transitional metal dichalcogenides, as a new genus of two-dimensional nanomaterials, have attracted tremendous attention in recent years, owing to their various intriguing properties. In this study, chemically exfoliated MoS2 nanosheets are modified with lipoic acid-terminated polyethylene glycol (LA-PEG), obtaining PEGylated MoS2 (MoS2-PEG) with high stability in physiological solutions and no obvious toxicity. Taking advantage of its ultra-high surface area, the obtained MoS2-PEG is able to load a photodynamic agent, chlorin e6 (Ce6), by physical adsorption. In vitro experiments reveal that Ce6 after being loaded on MoS2-PEG shows remarkably increased cellular uptake and thus significantly enhanced photodynamic

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

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.

[Photodynamic therapy of urinary bladder cancer using a chlorin based photosensitizer].

PubMed

Iagudaev, D M; Martov, A G; Sorokatyĭ, A E; Geĭnits, A V

2006-01-01

Photodynamic therapy (PDT) is a modem, low-invasive method of urinary bladder (UB) cancer treatment. PDT can induce complete or partial destruction of the tumor, reduce recurrence rate, provide assistance to elderly patients with compromised somatic status who are not radically operable. A combined technique improves the results of photodynamic therapy in patients with surface and invasive UB cancer of stage T2 because photodynamic impact affects not only the tumor but also all UB mucosa by light fiber with cylindric diffusor introduced in a silicon balloon with water. This leads to tumor destruction and a recurrence rate decrease.

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.

Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping.

PubMed

Schucht, Philippe; Beck, Jürgen; Abu-Isa, Janine; Andereggen, Lukas; Murek, Michael; Seidel, Kathleen; Stieglitz, Lennard; Raabe, Andreas

2012-11-01

Complete resection of contrast-enhancing tumor has been recognized as an important prognostic factor in patients with glioblastoma and is a primary goal of surgery. Various intraoperative technologies have recently been introduced to improve glioma surgery. To evaluate the impact of using 5-aminolevulinic acid and intraoperative mapping and monitoring on the rate of complete resection of enhancing tumor (CRET), gross total resection (GTR), and new neurological deficits as part of an institutional protocol. One hundred three consecutive patients underwent resection of glioblastoma from August 2008 to November 2010. Eligibility for CRET was based on the initial magnetic resonance imaging assessed by 2 reviewers. The primary end point was the number of patients with CRET and GTR. Secondary end points were volume of residual contrast-enhancing tissue and new postoperative neurological deficits. Fifty-three patients were eligible for GTR/CRET (n = 43 newly diagnosed glioblastoma, n = 10 recurrent); 13 additional patients received surgery for GTR/CRET-ineligible glioblastoma. GTR was achieved in 96% of patients (n = 51, no residual enhancement >0.175 cm); CRET was achieved in 89% (n = 47, no residual enhancement). Postoperatively, 2 patients experienced worsening of preoperative hemianopia, 1 patient had a new mild hemiparesis, and another patient sustained sensory deficits. Using 5-aminolevulinic acid imaging and intraoperative mapping/monitoring together leads to a high rate of CRET and an increased rate of GTR compared with the literature without increasing the rate of permanent morbidity. The combination of safety and resection-enhancing intraoperative technologies was likely to be the major drivers for this high rate of CRET/GTR.

Photodynamic detection in visualisation of cutaneous and oral mucosa premalignant and malignant lesions: two clinical cases

NASA Astrophysics Data System (ADS)

Jurczyszyn, Kamil; Ziólkowski, Piotr; Osiecka, Beata; Gerber, Hanna; Dziedzic, Magdalena

2008-11-01

Photodynamic diagnosis (PDD) is promising method of visualisation of premalignant and malignant lesions. PDD is consisted of two main agents: special chemical compound which is called photosensitizer and light. Photosensitizer has affinity to fast proliferating cells such as pre- or malignant. During light irradiation (with proper wavelength - corresponding to absorption peak of photosensitizer) photosensitizer gains energy and passes into excited singlet state S1. Returning to basic singlet state Sn, leads to fluorescence. Due to difference between concentration of photosensitizer in lesion and normal tissue it is possible to obtain high contrast image of lesion. Case #1: 53 years old woman with basal cell carcinoma (BCC) in nasal region; 20% delta-aminolevulinic acid as a precursor of photosensitizer on eucerin base was used. Case #2: 57 years old woman with multifocal oral leukoplakia on cheek mucosa and tongue; 2% chlorophyll gel as photosesitizer was used. All photographs were taken in white light without any filter and in blue and UV light with orange filter: in both cases the total area of the lesions appeared to be larger than it has been clinically observed. Thus, the PDD might be helpful in evaluation of margins of surgical excision of such lesions.

Thermosetting gel for the delivery of 5-aminolevulinic acid esters to the cervix.

PubMed

Collaud, Sabine; Peng, Qian; Gurny, Robert; Lange, Norbert

2008-07-01

5-Aminolevulinic acid (5-ALA)-mediated photodynamic therapy has been proposed as an alternative, cervix-sparing treatment for cervical intraepithelial neoplasia (CIN). In this context, topical application of 5-ALA to the cervix is beneficial due to the small necessary dose and its minimal side effects. Therefore, lipophilic 5-ALA esters, such as hexylaminolevulinate (HAL), have led to improved local bioavailability and therapeutic efficacy. Hydrogels have shown to be more appropriate for the local delivery of these derivatives, but due to the limited long-term stability of such formulations at 25 degrees C, the development of an extemporaneously prepared hydrogel targeting CIN can be advantageous. Therefore, a poloxamer 407 thermosetting gel, which is liquid at room temperature and becomes a semi-solid when in contact with the female genital tract, has been evaluated in vitro and in vivo. Rheological evaluation has shown that a 17.0% poloxamer 407 hydrogel with a sol-gel transition at 24.8 +/- 0.6 degrees C was the best formulation for easy application and optimal residence time. Furthermore, similarly to other hydrogels previously tested, such a formulation shows a more complete HAL release in vitro than conventional cream vehicles, and tends to increase porphyrin accumulation in nude mice skin. Finally, in vitro release profiles were correlated to the in vivo results.

Multitriggered Tumor-Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation.

PubMed

Zhang, Ning; Zhao, Fenfang; Zou, Qianli; Li, Yongxin; Ma, Guanghui; Yan, Xuehai

2016-11-01

Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Photodynamic therapy in treatment of severe oral lichen planus.

PubMed

Rabinovich, O F; Rabinovich, I M; Guseva, A V

2016-01-01

The aim of the study was to elaborate the rationale for the application of photodynamic therapy in complex treatment of patient with severe oral lichen planus. Complex clinical and laboratory examination and treatment was performed in 54 patients divided on 3 groups. Diagnosis of oral lichen planus was based on clinical, histological and immunohistochemical features. Group 1 received standard treatment, in the second group photodynamic therapy was conducted in addition to conventional treatment, patients in the third group received only photodynamic therapy. The study results proved photodynamic therapy to be useful tool in complex treatment of severe oral lichen planus.

Photodynamic Therapy Combined with Terbinafine Against Chromoblastomycosis and the Effect of PDT on Fonsecaea monophora In Vitro

PubMed Central

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

2014-01-01

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. PMID:25366276

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. © 2014 Japanese Dermatological Association.

Dual-triggered oxygen self-supply black phosphorus nanosystem for enhanced photodynamic therapy.

PubMed

Liu, Jintong; Du, Ping; Mao, Hui; Zhang, Lei; Ju, Huangxian; Lei, Jianping

2018-07-01

Nonspecific distribution of photosensitizer and the intrinsic hypoxic condition in the tumor microenvironment are two key factors limiting the efficacy of O 2 -dependent photodynamic therapy (PDT). Herein, a dual-triggered oxygen self-supported nanosystem using black phosphorus nanosheet (BPNS) as both photosensitizer and nanocarrier was developed to enhance PDT for tumors within hypoxic microenvironment. The BPNS platform was functionalized with folate and a blocker DNA duplex of 5'-Cy5-aptamer-heme/3'-heme labeled oligonucleotides. The resulting heme dimer could passivate its peroxidase activity. After specific recognition of aptamer-target, the quenched fluorescence is "turned" on by cellular adenosine triphosphate. The passivated nanosystem then activates the catalytic function towards excessive intracellular H 2 O 2 to generate O 2 essential to sustain BPNS-mediated PDT, leading to 8.7-fold and 7.5-fold increase of PDT efficacy in treating the hypoxic cell and tumor, respectively. Therefore, the dual-triggered oxygen self-supply nanosystem not only exerts tumor microenvironment-associated stimulus for enhanced PDT but also surmounts hypoxia-associated therapy resistance. Copyright © 2018 Elsevier Ltd. All rights reserved.

Natural extracellular nanovesicles and photodynamic molecules: is there a future for drug delivery?

PubMed

Kusuzaki, Katsuyuki; Matsubara, Takao; Murata, Hiroaki; Logozzi, Mariantonia; Iessi, Elisabetta; Di Raimo, Rossella; Carta, Fabrizio; Supuran, Claudiu T; Fais, Stefano

2017-12-01

Photodynamic molecules represent an alternative approach for cancer therapy for their property (i) to be photo-reactive; (ii) to be not-toxic for target cells in absence of light; (iii) to accumulate specifically into tumour tissues; (iv) to be activable by a light beam only at the tumour site and (v) to exert cytotoxic activity against tumour cells. However, to date their clinical use is limited by the side effects elicited by systemic administration. Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focussed on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment.

Spectral matching technology for light-emitting diode-based jaundice photodynamic therapy device

NASA Astrophysics Data System (ADS)

Gan, Ru-ting; Guo, Zhen-ning; Lin, Jie-ben

2015-02-01

The objective of this paper is to obtain the spectrum of light-emitting diode (LED)-based jaundice photodynamic therapy device (JPTD), the bilirubin absorption spectrum in vivo was regarded as target spectrum. According to the spectral constructing theory, a simple genetic algorithm as the spectral matching algorithm was first proposed in this study. The optimal combination ratios of LEDs were obtained, and the required LEDs number was then calculated. Meanwhile, the algorithm was compared with the existing spectral matching algorithms. The results show that this algorithm runs faster with higher efficiency, the switching time consumed is 2.06 s, and the fitting spectrum is very similar to the target spectrum with 98.15% matching degree. Thus, blue LED-based JPTD can replace traditional blue fluorescent tube, the spectral matching technology that has been put forward can be applied to the light source spectral matching for jaundice photodynamic therapy and other medical phototherapy.

Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review.

PubMed

Calixto, Giovana Maria Fioramonti; Bernegossi, Jéssica; de Freitas, Laura Marise; Fontana, Carla Raquel; Chorilli, Marlus

2016-03-11

Photodynamic therapy (PDT) is a promising alternative approach for improved cancer treatment. In PDT, a photosensitizer (PS) is administered that can be activated by light of a specific wavelength, which causes selective damage to the tumor and its surrounding vasculature. The success of PDT is limited by the difficulty in administering photosensitizers (PSs) with low water solubility, which compromises the clinical use of several molecules. Incorporation of PSs in nanostructured drug delivery systems, such as polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), gold nanoparticles (AuNPs), hydrogels, liposomes, liquid crystals, dendrimers, and cyclodextrin is a potential strategy to overcome this difficulty. Additionally, nanotechnology-based drug delivery systems may improve the transcytosis of a PS across epithelial and endothelial barriers and afford the simultaneous co-delivery of two or more drugs. Based on this, the application of nanotechnology in medicine may offer numerous exciting possibilities in cancer treatment and improve the efficacy of available therapeutics. Therefore, the aim of this paper is to review nanotechnology-based drug delivery systems for photodynamic therapy of cancer.

Silicon Phthalocyanines Axially Disubstituted with Erlotinib toward Small-Molecular-Target-Based Photodynamic Therapy.

PubMed

Chen, Juan-Juan; Huang, Yi-Zhen; Song, Mei-Ru; Zhang, Zhi-Hong; Xue, Jin-Ping

2017-09-21

Small-molecular-target-based photodynamic therapy-a promising targeted anticancer strategy-was developed by conjugating zinc(II) phthalocyanine with a small-molecular-target-based anticancer drug. To prevent self-aggregation and avoid problems of phthalocyanine isomerization, two silicon phthalocyanines di-substituted axially with erlotinib have been synthesized and fully characterized. These conjugates are present in monomeric form in various solvents as well as culture media. Cell-based experiments showed that these conjugates localize in lysosomes and mitochondria, while maintaining high photodynamic activities (IC 50 values as low as 8 nm under a light dose of 1.5 J cm -2 ). With erlotinib as the targeting moiety, two conjugates were found to exhibit high specificity for EGFR-overexpressing cancer cells. Various poly(ethylene glycol) (PEG) linker lengths were shown to have an effect on the photophysical/photochemical properties and on in vitro phototoxicity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

5-Aminolevulinic Acid Induced Fluorescence Is a Powerful Intraoperative Marker for Precise Histopathological Grading of Gliomas with Non-Significant Contrast-Enhancement

PubMed Central

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A.; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Background Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. Methods We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. Results A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Conclusions Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift. PMID:24204718

5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement.

PubMed

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift.

Folate and Heptamethine Cyanine Modified Chitosan-Based Nanotheranostics for Tumor Targeted Near-Infrared Fluorescence Imaging and Photodynamic Therapy.

PubMed

Zhang, Yingying; Lv, Tingting; Zhang, Huijuan; Xie, Xiaodong; Li, Ziying; Chen, Haijun; Gao, Yu

2017-07-10

Folate (FA) and heptamethine cyanine (Cy7)-modified chitosan (CF7) was synthesized by click chemistry and its self-assembled nanoparticles (CF7Ns) were developed for tumor-specific imaging and photodynamic therapy. The characterization spectrum confirmed CF7 had a good FA and Cy7 conjugation efficacy. The diameter of CF7Ns measured by DLS was about 291.6 nm, and the morphology observed with AFM showed filamentous clusters of particles. The results of targeting ability of CF7Ns demonstrated enhanced targeting behaviors of CF7Ns compared with non-FA-modified nanoparticles C7Ns in FA receptor-positive HeLa cells. The cytotoxicity and cell apoptosis assay showed that CF7Ns under near-infrared light irradiation led to more apoptotic cell death in HeLa cells to improve the therapeutic efficacy. The mechanisms of the photodynamic effects of CF7Ns were demonstrated through measurement of intracellular reactive oxygen species and the apoptosis-related cytokines. These results suggested that CF7Ns are promising tumor targeting carriers for simultaneous fluorescence imaging and photodynamic therapy.

The natural flavonoid silybin improves the response to Photodynamic Therapy of bladder cancer cells.

PubMed

Gándara, L; Sandes, E; Di Venosa, G; Prack Mc Cormick, B; Rodriguez, L; Mamone, L; Batlle, A; Eiján, A M; Casas, A

2014-04-05

Photodynamic Therapy (PDT) is an anticancer treatment based on photosensitisation of malignant cells. The precursor of the photosensitiser Protoporphyrin IX, 5-aminolevulinic acid (ALA), has been used for PDT of bladder cancer. Silybin is a flavonoid extracted from Silybum marianum, and it has been reported to increase the efficacy of several anticancer treatments. In the present work, we evaluated the cytotoxicity of the combination of ALA-PDT and silybin in the T24 and MB49 bladder cancer cell lines. MB49 cells were more sensitive to PDT damage, which was correlated with a higher Protoporphyrin IX production from ALA. Employing lethal light doses 50% (LD50) and 75% (LD75) and additional silybin treatment, there was a further increase of toxicity driven by PDT in both cell lines. Using the Chou-Talalay model for drug combination derived from the mass-action law principle, it was possible to identify the effect of the combination as synergic when using LD75, whilst the use of LD50 led to an additive effect on MB49 cells. On the other hand, the drug combination turned out to be nearly additive on T24 cells. Apoptotic cell death is involved both in silybin and PDT cytotoxicity in the MB49 line but there is no apparent correlation with the additive or synergic effect observed on cell viability. On the other hand, we found an enhancement of the PDT-driven impairment of cell migration on both cell lines as a consequence of silybin treatment. Overall, our results suggest that the combination of silybin and ALA-PDT would increase PDT outcome, leading to additive or synergistic effects and possibly impairing the occurrence of metastases. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

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.

Real-time analysis of endogenous protoporphyrin IX fluorescence from δ-aminolevulinic acid and its derivatives reveals distinct time- and dose-dependent characteristics in vitro

NASA Astrophysics Data System (ADS)

Kiesslich, Tobias; Helander, Linda; Illig, Romana; Oberdanner, Christian; Wagner, Andrej; Lettner, Herbert; Jakab, Martin; Plaetzer, Kristjan

2014-08-01

Photodynamic therapy (PDT) and photodiagnosis based on the intracellular production of the photosensitizer protoporphyrin IX (PPIX) by administration of its metabolic precursor δ-aminolevulinic acid (ALA) achieved their breakthrough upon the clinical approval of MAL (ALA methyl ester) and HAL (ALA hexyl ester). For newly developed ALA derivatives or application in new tumor types, in vitro determination of PPIX formation involves multiparametric experiments covering variable pro-drug concentrations, medium composition, time points of analysis, and cell type(s). This study uses a fluorescence microplate reader with a built-in temperature and atmosphere control to investigate the high-resolution long-term kinetics (72 h) of cellular PPIX fueled by administration of either ALA, MAL, or HAL for each 10 different concentrations. For simultaneous proliferation correction, A431 cells were stably transfected with green fluorescent protein. The results indicate that the peak PPIX level is a function of both, incubation concentration and period: maximal PPIX is generated with 1 to 2-mM ALA/MAL or 0.125-mM HAL; also, the PPIX peak shifts to longer incubation periods with increasing pro-drug concentrations. The results underline the need for detailed temporal analysis of PPIX formation to optimize ALA (derivative)-based PDT or photodiagnosis and highlight the value of environment-controlled microplate readers for automated in vitro analysis.

Diketopyrrolopyrrole-based carbon dots for photodynamic therapy.

PubMed

He, Haozhe; Zheng, Xiaohua; Liu, Shi; Zheng, Min; Xie, Zhigang; Wang, Yong; Yu, Meng; Shuai, Xintao

2018-06-01

The development of a simple and straightforward strategy to synthesize multifunctional carbon dots for photodynamic therapy (PDT) has been an emerging focus. In this work, diketopyrrolopyrrole-based fluorescent carbon dots (DPP CDs) were designed and synthesized through a facile one-pot hydrothermal method by using diketopyrrolopyrrole (DPP) and chitosan (CTS) as raw materials. DPP CDs not only maintained the ability of DPP to generate singlet oxygen (1O2) but also have excellent hydrophilic properties and outstanding biocompatibility. In vitro and in vivo experiments demonstrated that DPP CDs greatly inhibited the growth of tumor cells under laser irradiation (540 nm). This study highlights the potential of the rational design of CDs for efficient cancer therapy.

5-Aminolevulinic Acid-Squalene Nanoassemblies for Tumor Photodetection and Therapy: In Vitro Studies

NASA Astrophysics Data System (ADS)

Babič, Andrej; Herceg, V.; Bastien, E.; Lassalle, H.-P.; Bezdetnaya, L.; Lange, Norbert

2018-01-01

Protoporphyrin IX (PpIX) as natural photosensitizer derived from administration of 5-aminolevulinic acid (5-ALA) has found clinical use for photodiagnosis and photodynamic therapy of several cancers. However, broader use of 5-ALA in oncology is hampered by its charge and polarity that result in its reduced capacity for passing biological barriers and reaching the tumor tissue. Advanced drug delivery platforms are needed to improve the biodistribution of 5-ALA. Here, we report a new approach for the delivery of 5-ALA. Squalenoylation strategy was used to covalently conjugate 5-ALA to squalene, a natural precursor of cholesterol. 5-ALA-SQ nanoassemblies were formed by self-assembly in water. The nanoassemblies were monodisperse with average size of 70 nm, polydispersity index of 0.12, and ζ-potential of + 36 mV. They showed good stability over several weeks. The drug loading of 5-ALA was very high at 26%. In human prostate cancer cells PC3 and human glioblastoma cells U87MG, PpIX production was monitored in vitro upon the incubation with nanoassemblies. They were more efficient in generating PpIX-induced fluorescence in cancer cells compared to 5-ALA-Hex at 1.0 to 3.3 mM at short and long incubation times. Compared to 5-ALA, they showed superior fluorescence performance at 4 h which was diminished at 24 h. 5-ALA-SQ presents a novel nano-delivery platform with great potential for the systemic administration of 5-ALA.

Photodynamic therapy and knocking out of single tumor cells by multiphoton excitation processes

NASA Astrophysics Data System (ADS)

Riemann, Iris; Fischer, Peter; Koenig, Karsten

2004-09-01

Near infrared (NIR) ultrashort laser pulses of 780 nm have been used to induce intracellular photodynamic reactions by nonlinear excitation of porphyrin photosensitizers. Intracellular accumulation and photobleaching of the fluorescent photosensitizers protoporphyrin IX and Photofrin (PF) have been studied by non-resonant two-photon fluorescence excitation of PF and aminolevulinic acid (ALA)-labeled Chinese hamster ovary (CHO) cells. To testify the efficacy of both substrates to induce irreversible destructive effects, the cloning efficiency (CE) of cells exposed to femtosecond pulses of a multiphoton laser scanning microscope (40x/1.3) was determined. In the case of Photofrin accumulation, CEs of 50% and 0% were obtained after 17 laserscans (2 mW?, 16 s/ frame) and 50 scans, respectively. All cells exposed to 50 scans died within 48h after laser exposure. 100 scans were required to induce lethal effects in ALA labeled cells. Sensitizer-free control cells could be scanned 250 times (1.1 h) and more without impact on the reproduction behavior, morphology, and vitality. In addition to the slow phototoxic effect by photooxidation processes, another destructive but immediate effect based on optical breakdown was induced when employing high intense NIR femtosecond laser beams. This was used to optically knock out single tumor cells in living mice (solid Ehrlich-Carcinoma) in a depth of 10 to 100 μm.

Photodynamic diagnostics of stress-induced gastrointestinal neoplasia in laboratory animals using 5-aminolevulinic acid and Al-phthalocyanine

NASA Astrophysics Data System (ADS)

Borisova, Ekaterina; Semyachkina-Glushkovskaya, Oxana; Navolokin, Nikita; Mantareva, Vanya; Angelov, Ivan; Agranovich, Ilana; Khorovodov, Alexander; Shushunova, Natalia; Bodrova, Anastasiya; Fedosov, Ivan; Namykin, Anton; Abdurashitov, Arkady; Avramov, Latchezar

2018-02-01

The main research objective is the development of innovative optical technologies for sensitive diagnosis of early stages of development of stomach cancer and monitoring of stress-induced appearance and development of tumors of the gastrointestinal tract by applying endogenous and exogenous fluorescence spectroscopy modalities. Different mechanisms solely and in combination for evaluation of the joint impact of bioenvironmental factors (stress, Helicobacter pillory, exo-toxins in the food, water, soil and air) were applied to induce gastrointestinal tract (GIT) neoplasia in rats. The transformation of damaged areas of the stomach mucosa into malignancies in all parts of gastrointestinal tract were detected using exogenous fluorescence of photosensitizers - 5-aminolevulinic acid (5-ALA) and aluminum phthalocyanine (Al-Pc). Fluorescent mapping of different organs (liver, spleen, lungs, brain) also was developed - to evaluate the distribution of the photosensitizers in the whole body on the second hour after photosensitizer application by intravenous injection. Fiber-optic probe was used to measure the organs investigated. Fluorescence spectra were detected by microspectrometer USB4000 (OceanOptics Inc., USA), and FS405 LED source on 405 nm was used as excitation source for both types of photosensitizers applied. Diagnostically-important parameters of oximetry, optical coherence tomography and speckle-imaging of the microcirculation of the stomach were also evaluated, to evaluate changes in the blood flow and vascular architecture, during the formation of the initial phases of the neoplasm development.

Inhibitory Effect of Gabaculine on 5-Aminolevulinate Dehydratase Activity in Radish Seedlings 1

PubMed Central

Tchuinmogne, Simo J.; Huault, Claude; Aoues, Abdelkader; Balangé, Alain P.

1989-01-01

We have compared the activity of 5-aminolevulinate dehydratase (5-ALAD) with the amount of protein detected by specific antibodies in rocket immunoelectrophoresis. Parallel kinetic evolutions of enzymic activity and amount of antigen were observed in radish (Raphanus sativus L.) cotyledons, both in complete darkness or under standard far red light involving phytochrome. However, the treatment of seedlings with gabaculine leads to an important decrease in enzymic activity, while the specific protein content is maintained. This inhibition is not overcome by the addition of glutamic acid, but by 5-aminolevulinic acid which points to a specific control of 5-ALAD activity by its substrate. As there is no discrepancy between the enzymic activity and the amount of antigen during the time course development of seedlings, this could confirm a coordinate cellular control between 5-aminolevulinic acid formation and 5-ALAD protein synthesis, both being amplified by the action of phytochrome. PMID:16666925

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.

Self-assembled nanoparticles based on PEGylated conjugated polyelectrolyte and drug molecules for image-guided drug delivery and photodynamic therapy.

PubMed

Yuan, Youyong; Liu, Bin

2014-09-10

A drug delivery system based on poly(ethylene glycol) (PEG) grafted conjugated polyelectrolyte (CPE) has been developed to serve as a polymeric photosensitizer and drug carrier for combined photodynamic and chemotherapy. The amphiphilic brush copolymer can self-assemble into micellar nanopaticles (NPs) in aqueous media with hydrophobic conjugated polyelectrolyte backbone as the core and hydrophilic PEG as the shell. The NPs have an average diameter of about 100 nm, with the absorption and emission maxima at 502 and 598 nm, respectively, making them suitable for bioimaging applications. Moreover, the CPE itself can serve as a photosensitizer, which makes the NPs not only a carrier for drug but also a photosensitizing unit for photodynamic therapy, resulting in the combination of chemo- and photodynamic therapy for cancer. The half-maximal inhibitory concentration (IC50) value for the combination therapy to U87-MG cells is 12.7 μg mL(-1), which is much lower than that for the solely photodynamic therapy (25.5 μg mL(-1)) or chemotherapy (132.8 μg mL(-1)). To improve the tumor specificity of the system, cyclic arginine-glycine-aspartic acid (cRGD) tripeptide as the receptor to integrin αvβ3 overexpressed cancer cells was further incorporated to the surface of the NPs. The delivery system based on PEGylated CPE is easy to fabricate, which integrates the merits of targeted cancer cell image, chemotherapeutic drug delivery, and photodynamic therapy, making it promising for cancer treatment.

IR780 based nanomaterials for cancer imaging and photothermal, photodynamic and combinatorial therapies.

PubMed

Alves, Cátia G; Lima-Sousa, Rita; de Melo-Diogo, Duarte; Louro, Ricardo O; Correia, Ilídio J

2018-05-05

IR780, a molecule with a strong optical absorption and emission in the near infrared (NIR) region, is receiving an increasing attention from researchers working in the area of cancer treatment and imaging. Upon irradiation with NIR light, IR780 can produce reactive oxygen species as well as increase the body temperature, thus being a promising agent for application in cancer photodynamic and photothermal therapy. However, IR780's poor water solubility, fast clearance, acute toxicity and low tumor uptake may limit its use. To overcome such issues, several types of nanomaterials have been used to encapsulate and deliver IR780 to tumor cells. This mini-review is focused on the application of IR780 based nanostructures for cancer imaging, and photothermal, photodynamic and combinatorial therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

Photodynamic Therapy for Cancer Cells Using a Flash Wave Light Xenon Lamp

NASA Astrophysics Data System (ADS)

Kimura, Makoto; Kashikura, Kasumi; Yokoi, Satomi; Koiwa, Yumiko; Tokuoka, Yoshikazu; Kawashima, Norimichi

We determined photodynamic therapy (PDT) efficacy using a flash wave (FW) and a continuous wave (CW) light, of which the fluence rate was 70 W/cm2, for murine thymic lymphoma cells (EL-4) cultivated in vitro. The irradiation frequency and the pulse width of the FW light were in the range of 1-32 Hz and less than one millisecond, respectively. 5-Aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX) was used as a photosensitizer. When EL-4 with ALA administration was irradiated by the light for 4 h (irradiation fluence: 1.0J/cm2), the survival rate of EL-4 by the FW light was lower than that by the CW light, except for the FW light with irradiation frequency of 32 Hz, and decreased gradually with decreasing irradiation frequency. Moreover, the FW light, especially at lower irradiation frequency, was superior to the CW light for the generation of singlet oxygen in an aqueous PpIX solution. Therefore, thehigher PDT efficacy for EL-4 of the FW light would be caused by the greater generation of singlet oxygen in the cells.

Experimental lead intoxication in dogs: a comparison of blood lead and urinary delta-aminolevulinic acid following intoxication and chelation therapy.

PubMed Central

Green, R A; Selby, L A; Zumwalt, R W

1978-01-01

Intravenous lead administration to dogs produced an acute syndrome of lead intoxication charcterized by depression, vomiting, anorexia and weight loss. The effect of chelation therapy with calcium disodium ethylene diamine tetraacetate, penicillamine or both was determined by serially monitoring changes in blood lead and urine delta-aminolevulinic acid. Following therapy, blood lead values were significantly lower in chelated dogs than non-treated lead exposed dogs on days 7 and 10. Urine delta-aminolevulinic acid at day 7 was significantly higher in untreated lead exposed dogs than in other groups. There was no significant difference in blood lead or urine delta-aminolevulinic acid between lead intoxicated dogs which underwent the indicated chelation therapy protocols. There was, however, a trend for higher urinary delta-aminolevulinic acid excretion in those intoxicated dogs undergoing calcium disodium ethylene diamine tetraacetate therapy as opposed to those undergoing penicilamine therapy. There was no significant correlation between blood lead and urinary delta-aminolevulinic acid previous to lead exposure. However, after lead exposure significant correlation was present at days 4, 7, 10 and 14. Certain lead exposed dogs following chelation therapy were noted to have normal blood lead levels but elevated urinary delta-aminolevulinic acid suggesting that blood lead does not always correlate with metabolic effects of lead in the body. Urinary delta-aminolevulinic acid was therefore recommended as an additional laboratory parameter which improved assessment of lead exposure in dogs, particularly in determining adequacy of chelation therapy. PMID:667707

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.

Two-step irradiance schedule versus single-dose tramadol sustained-release tablets for pain control during topical 5-aminolevulinic acid-photodynamic therapy of condyloma acuminatum in Chinese patients: a randomized comparative study.

PubMed

Mchepange, Uwesu O; Huang, Chun-Yan; Sun, Yi; Tu, Ya-Ting; Tao, Juan

2014-07-01

Photodynamic therapy with 5-aminolevulinic acid (ALA-PDT) offers promising results for the treatment of condyloma acuminatum. However, patients have to dwell with pain to benefit from this otherwise effective and safe "off-label" treatment modality. Several techniques have been explored to control ALA-PDT-induced pain, but the desperate search for a universally accepted method is still ongoing. This study compares the two-step irradiance approach with single-dose administration of 100 mg tramadol sustained-release tablets for pain induced by ALA-PDT of condyloma acuminatum in Chinese patients. Adult Chinese patients with condyloma acuminatum were enrolled in a randomized comparative study. Pain levels were compared using the Numeric Rating Scale (NRS) at pre-defined assessment points during and after irradiation. The pain was dominated by characteristics such as burning and pricking and was almost always local and superficial. The median pain scores were lower in the two-step irradiance group at 1 minute (U = 621.5, P = 0.002) but higher at 20 minutes (U = 585.5, P = 0.002). The median pain scores between the two groups did not differ significantly at other assessment points. The pain was moderate in both groups and peaked earlier in the analgesics group (median: 5 minutes) but later in the two-step irradiance group (median: 15 minutes). The pain was generally mild. The median pain scores were equal at each assessment point, except at 3 hours where the median was lower in the analgesics group (1.0) as compared with the two-step irradiance group (2.0) (U = 725.0, P = 0.056). Pain in the two-step irradiance protocol is irradiance-dependent. The two-step irradiance approach produces significant benefits over analgesics during the initial stages of therapy but analgesics offer significant benefits thereafter. There are potential benefits of combining the two approaches in minimizing ALA-PDT-induced pain. © 2014 Wiley Periodicals

ALA-induced photodynamic effect on vitality, apoptosis, and secretion of vascular endothelial growth factor (VEGF) by colon cancer cells in normoxic environment in vitro.

PubMed

Kawczyk-Krupka, A; Sieroń-Stołtny, K; Latos, W; Czuba, Z P; Kwiatek, B; Potempa, M; Wasilewska, K; Król, W; Stanek, A

2016-03-01

Cancer therapy is often based on combination of conventional methods of cancer treatment with immunotherapy. Photodynamic therapy (PDT) is one of the immunomodulating methods used in oncology. We examined how PDT influences the secretory activity of colon cancer cells in vitro, especially the secretion of vascular endothelial growth factor (VEGF) in aerobic conditions. We used two cancer cell lines with different malignancy potentials: a metastatic SW620 line and a non-metastatic SW480 line. In the first stage of the experiment, we exposed each cell line to three different concentrations of photosensitizer's precursor: 5-aminolevulinic acid (ALA) and varying levels of light radiation, after which we assessed cell viability and apoptosis induction in these lines, using the MTT and LDH assays. Then, we determined the secretion of VEGF by these cells in aerobic conditions and under the ALA-PDT parameters at which cells presented the highest viability. Photodynamic treatment with ALA did not influence on VEGF secretion by the non-metastatic SW480 cells, but caused a decrease in VEGF secretion by the metastatic SW 620 cell line by 29% (p<0.05). SW 620 cell line secreted more actively VEGF than the SW480 cells, both before and after photo dynamic therapy (p<0.05). The outcome of this in vitro study presented a beneficial effect of ALA-PDT, resulting in a decrease of VEGF secretion in the more malignant SW620 cell lines. Further studies should be considered to confirm the clinical relevance of this finding. Copyright © 2015 Elsevier B.V. All rights reserved.

Enhanced systemic immune reactivity to a Basal cell carcinoma associated antigen following photodynamic therapy.

PubMed

Kabingu, Edith; Oseroff, Allan R; Wilding, Gregory E; Gollnick, Sandra O

2009-07-01

Numerous preclinical studies have shown that local photodynamic therapy (PDT) of tumors enhances systemic antitumor immunity. However, other than single-case and anecdotal reports, this phenomenon has not been examined following clinical PDT. To determine whether PDT in a clinical setting enhances systemic recognition of tumor cells, we examined whether PDT of basal cell carcinoma resulted in an increased systemic immune response to Hip1, a tumor antigen associated with basal cell carcinoma. Basal cell carcinoma lesions were either treated with PDT or surgically removed. Blood was collected from patients immediately before or 7 to 10 days following treatment. Peripheral blood leukocytes were isolated from HLA-A2-expressing patients and reactivity to a HLA-A2-restricted Hip1 peptide was measured by INF-gamma ELISpot assay. Immune recognition of Hip1 increased in patients whose basal cell carcinoma lesions were treated with PDT. This increase in reactivity was significantly greater than reactivity observed in patients whose lesions were surgically removed. Patients with superficial lesions exhibited greater enhancement of reactivity compared with patients with nodular lesions. Immune reactivity following PDT was inversely correlated with treatment area and light dose. These findings show for the first time that local tumor PDT can enhance systemic immune responses to tumors in patients, and validate previous preclinical findings.

A graphene oxide based smart drug delivery system for tumor mitochondria-targeting photodynamic therapy

NASA Astrophysics Data System (ADS)

Wei, Yanchun; Zhou, Feifan; Zhang, Da; Chen, Qun; Xing, Da

2016-02-01

Subcellular organelles play critical roles in cell survival. In this work, a novel photodynamic therapy (PDT) drug delivery and phototoxicity on/off nano-system based on graphene oxide (NGO) as the carrier is developed to implement subcellular targeting and attacking. To construct the nanodrug (PPa-NGO-mAb), NGO is modified with the integrin αvβ3 monoclonal antibody (mAb) for tumor targeting. Pyropheophorbide-a (PPa) conjugated with polyethylene-glycol is used to cover the surface of the NGO to induce phototoxicity. Polyethylene-glycol phospholipid is loaded to enhance water solubility. The results show that the phototoxicity of PPa on NGO can be switched on and off in organic and aqueous environments, respectively. The PPa-NGO-mAb assembly is able to effectively target the αvβ3-positive tumor cells with surface ligand and receptor recognition; once endocytosized by the cells, they are observed escaping from lysosomes and subsequently transferring to the mitochondria. In the mitochondria, the `on' state PPa-NGO-mAb performs its effective phototoxicity to kill cells. The biological and physical dual selections and on/off control of PPa-NGO-mAb significantly enhance mitochondria-mediated apoptosis of PDT. This smart system offers a potential alternative to drug delivery systems for cancer therapy.Subcellular organelles play critical roles in cell survival. In this work, a novel photodynamic therapy (PDT) drug delivery and phototoxicity on/off nano-system based on graphene oxide (NGO) as the carrier is developed to implement subcellular targeting and attacking. To construct the nanodrug (PPa-NGO-mAb), NGO is modified with the integrin αvβ3 monoclonal antibody (mAb) for tumor targeting. Pyropheophorbide-a (PPa) conjugated with polyethylene-glycol is used to cover the surface of the NGO to induce phototoxicity. Polyethylene-glycol phospholipid is loaded to enhance water solubility. The results show that the phototoxicity of PPa on NGO can be switched on and off in

Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tasmin, Saira, E-mail: rimzim1612@yahoo.com; Furusawa, Hana; Ahmad, Sk. Akhtar

Background and objective: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. Methods: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected tomore » determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). Results: The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1carriers. Conclusion: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. - Highlights: • High blood lead level for the environmentally exposed schoolchildren. • BPb was significantly correlated with U-ALA and Hb. • Effect of ALAD genotype on U-ALA is differed by sex. • Lower U-ALA in ALAD2 than ALAD1 carriers only for boys at same exposure.« less

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.

Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy

NASA Astrophysics Data System (ADS)

Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

2016-06-01

Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer.Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser

CT contrast predicts pancreatic cancer treatment response to verteporfin-based photodynamic therapy

NASA Astrophysics Data System (ADS)

Jermyn, Michael; Davis, Scott C.; Dehghani, Hamid; Huggett, Matthew T.; Hasan, Tayyaba; Pereira, Stephen P.; Bown, Stephen G.; Pogue, Brian W.

2014-04-01

The goal of this study was to determine dominant factors affecting treatment response in pancreatic cancer photodynamic therapy (PDT), based on clinically available information in the VERTPAC-01 trial. This trial investigated the safety and efficacy of verteporfin PDT in 15 patients with locally advanced pancreatic adenocarcinoma. CT scans before and after contrast enhancement from the 15 patients in the VERTPAC-01 trial were used to determine venous-phase blood contrast enhancement and this was correlated with necrotic volume determined from post-treatment CT scans, along with estimation of optical absorption in the pancreas for use in light modeling of the PDT treatment. Energy threshold contours yielded estimates for necrotic volume based on this light modeling. Both contrast-derived venous blood content and necrotic volume from light modeling yielded strong correlations with observed necrotic volume (R2 = 0.85 and 0.91, respectively). These correlations were much stronger than those obtained by correlating energy delivered versus necrotic volume in the VERTPAC-01 study and in retrospective analysis from a prior clinical study. This demonstrates that contrast CT can provide key surrogate dosimetry information to assess treatment response. It also implies that light attenuation is likely the dominant factor in the VERTPAC treatment response, as opposed to other factors such as drug distribution. This study is the first to show that contrast CT provides needed surrogate dosimetry information to predict treatment response in a manner which uses standard-of-care clinical images, rather than invasive dosimetry methods.

[Application of photodynamic therapy in dentistry – literature review].

PubMed

Oruba, Zuzanna; Chomyszyn-Gajewska, Maria

Photodynamic therapy (PDT) is based on the principle that the target cells are destroyed by means of toxic reactive oxygen species generated upon the interaction of a photosensitizer, light and oxygen. This method is nowadays widely applied in various branches of medicine, mainly in oncology and dermatology. It is also applied in dentistry in the treatment of oral potentially malignant disorders (like lichen planus or leukoplakia) and infectious conditions (periodontitis, herpetic cheilitis, root canal disinfection). The application of the photodynamic therapy in the abovementioned indications is worth attention, as the method is noninvasive, painless, and the results of the published studies seem promising. The present article aims at presenting the principle of the photodynamic therapy and, based on the literature, the possibilities and results of its application in dentistry.

Photodynamic effects of pyropheophorbide-a methyl ester in nasopharyngeal carcinoma cells.

PubMed

Xu, Chuan Shan; Leung, Albert Wing Nang

2006-08-01

Nasopharyngeal carcinoma (NPC) is one of the most common cancers, and exploring novel therapeutic modalities will improve the clinical outcomes. It has been confirmed that photodynamic therapy can efficiently deactivate malignant cells. The aim of the present study was to explore the photodynamic effects of pyropheophorbide-a methyl ester (MPPa) in CNE2 nasopharyngeal carcinoma cells. CNE2 cells were subjected to photodynamic therapy with MPPa, in which the drug concentration was 0.25 to 4 microM and light energy 1 to 8 J/cm(2). Photodynamic toxicity was investigated 24 h after treatment. Apoptosis was determined using flow cytometry with annexin V-FITC and propidum iodine staining and with nuclear staining with Hoechst 33258. The mitochondrial membrane potential (DeltaPsim) was evaluated by Rhodamine 123 assay. There was no dark cytotoxicity of MPPa in the CNE2 cells at doses of 0.25-4 microM, and MPPa resulted in dose- and light-dependent phototoxicity. The apoptotic rate 8 h after PDT with MPPa (2 microM) increased to 16.43% under a light energy of 2 J/cm(2). Mitochondrial membrane potential (DeltaPsim) collapsed when the CNE2 cells were exposed to 2 microM MPPa for 20 h and then 2 J/cm(2) irradiation. Photodynamic therapy with MPPa significantly enhanced apoptosis and the collapse of DeltaPsim. This can be developed for treating nasopharyngeal carcinoma.

Progress toward development of photodynamic vaccination against infectious/malignant diseases and photodynamic mosquitocides

NASA Astrophysics Data System (ADS)

Chang, Kwang Poo; Kolli, Bala K.; Fan, Chia-Kwung; Ng, Dennis K. P.; Wong, Clarence T. T.; Manna, Laura; Corso, Raffaele; Shih, Neng-Yao; Elliott, Robert; Jiang, X. P.; Shiao, Shin-Hong; Fu, Guo-Liang

2018-02-01

Photodynamic therapy (PDT) uses photosensitizers (PS) that are excited with light to generate ROS in the presence of oxygen for treating various diseases. PS also has the potential use as photodynamic insecticides (PDI) and for light-inactivation of Leishmania for photodynamic vaccination (PDV). PDT-inactivated Leishmania are non-viable, but remain immunologically competent as whole-cell vaccines against leishmaniasis, and as a universal carrier for delivery of add-on vaccines against other infectious and malignant diseases. We have screened novel PS, including Zn- and Si-phthalocyanines (PC) for differential PDT activities against Leishmania, insect and mammalian cells in vitro to assess their PDI and PDV potential. Here, Zn-PC were conjugated with various functional groups. The conjugates were examined for uptake by cells as a prerequisite for their susceptibility to light-inactivation. PDT sensitivity was found to vary with cell types and PS used. PDI potential of several PS was demonstrated by their mosquito larvicidal PDT activities in vitro. PDT-inactivated Leishmania were stored frozen for PDV in several ongoing studies: [1] Open label trial with 20 sick dogs for immunotherapy of canine leishmaniasis after chemotherapy in Naples, Italy. Clinical follow-up for >3 years indicate that the PDV prolongs their survival; [2] PDV of murine models with a human lung cancer vaccine showed dramatic tumor suppression; [3] Open label trial of multiple PDV via compassionate access to 4 advanced cancer patients showed no clinically adverse effects. Two subjects remain alive. Genetic modifications of Leishmania are underway to further enhance their safety and efficacy for PDV by installation of activable mechanisms for self-destruction and spontaneous light-emission.

5-Aminolevulinic Acid (ALA) Alleviated Salinity Stress in Cucumber Seedlings by Enhancing Chlorophyll Synthesis Pathway.

PubMed

Wu, Yue; Jin, Xin; Liao, Weibiao; Hu, Linli; Dawuda, Mohammed M; Zhao, Xingjie; Tang, Zhongqi; Gong, Tingyu; Yu, Jihua

2018-01-01

5-Aminolevulinic acid (ALA) is a common precursor of tetrapyrroles as well as a crucial growth regulator in higher plants. ALA has been proven to be effective in improving photosynthesis and alleviating the adverse effects of various abiotic stresses in higher plants. However, little is known about the mechanism of ALA in ameliorating the photosynthesis of plant under abiotic stress. In this paper, we studied the effects of exogenous ALA on salinity-induced damages of photosynthesis in cucumber ( Cucumis sativus L.) seedlings. We found that the morphology (plant height, leave area), light utilization capacity of PS II [qL, Y(II)] and gas exchange capacity (Pn, gs, Ci, and Tr) were significantly retarded under NaCl stress, but these parameters were all recovered by the foliar application of 25 mg L -1 ALA. Besides, salinity caused heme accumulation and up-regulation of gene expression of ferrochelatase ( HEMH ) with suppression of other genes involved in chlorophyll synthesis pathway. Exogenously application of ALA under salinity down-regulated the heme content and HEMH expression, but increased the gene expression levels of glutamyl-tRNA reductase ( HEMA1 ), Mg-chelatase ( CHLH ), and protochlorophyllide oxidoreductase ( POR ). Moreover, the contents of intermediates involved in chlorophyll branch were increased by ALA, including protoporphyrin IX (Proto IX), Mg-protoporphyrin IX (Mg-Proto IX, protochlorophyllide (Pchlide), and chlorophyll (Chl a and Chl b ) under salt stress. Ultrastructural observation of mesophyll cell showed that the damages of photosynthetic apparatus under salinity were fixed by ALA. Collectively, the chlorophyll biosynthesis pathway was enhanced by exogenous ALA to improve the tolerance of cucumber under salinity.

Photodynamic therapy platform for glioblastoma and intrabronchial tumors

NASA Astrophysics Data System (ADS)

Orsila, Lasse; Alanko, Jukka-Pekka; Kaivosoja, Visa; Uibu, Toomas

2018-02-01

Photodynamic therapy (PDT) is bringing new, effective, and less invasive, possibilities for cancer treatment. ML7710 (Modulight Inc.) medical laser system offers a platform for performing PDT for multiple indications and drugs. Latest avenue is glioblastoma treatment with 5-Aminolevulinic acid (ALA-5) and 635-nm light, where clinical trials are about to begin. Preliminary work suggests major advantages in treatment control, including active in-situ feedback. ML7710 platform has already proven itself for clinical work with intrabronchial obstructive tumors. Preliminary result with 10 patients show that intrabronchial tumors, that strongly affect both the survival and the performance of the patient, can be significantly reduced with ML7710 operated at 665 nm and sodium chlorine E6 photosensitizer. The aim in most of the patients has been a palliative recanalization of the bronchial lumen in order to alleviate the symptoms such as breathlessness and hemoptysis. The illumination dose for the target area was 50-75 J/cm2. All the patients have received multimodality cancer treatment using other intrabronchial interventions, radiotherapy and chemotherapy as needed. In most of the patients, satisfactory treatment results were achieved and it was possible to restart chemotherapy in several patients. In one patient with local cancer a complete remission was established. PDT has also the advantage that it is possible to give PDT after a maximum dose of radiation therapy has already been used and fewer side effects if used in locally advanced intraluminar lung cancer.

Vitamin D for combination photodynamic therapy of skin cancer in individuals with vitamin D deficiency: Insights from a preclinical study in a mouse model of squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Anand, Sanjay; Thomas, Erik; Hasan, Tayyaba; Maytin, Edward V.

2016-03-01

Combination photodynamic therapy (cPDT) in which vitamin D (VD) is given prior to aminolevulinate, a precursor (pro-drug) for protoporphyrin IX (PpIX), is an approach developed in our laboratory. We previously showed that 1α,25- dihydroxyvitamin D3 (calcitriol), given prior to PDT, enhances accumulation of PpIX and improves cell death post-PDT in a mouse skin cancer model. However, since calcitriol poses a risk for hypercalcemia, we replaced systemic calcitriol with oral cholecalciferol (D3), administered as a high (tenfold, "10K") diet over a ten-day period. Here, we ask whether VD deficiency might alter the response to cPDT. Nude mice were fed a VD-deficient diet for at least 4 weeks ("deficient"); controls were fed a normal 1,000 IU/kg diet ("1K"). Human A431 cells were implanted subcutaneously and mice were switched to the 10K diet or continued on their baseline diets (controls). In other experiments, mice received a human equivalent dose of 50,000 IU D3 by oral gavage, to simulate administration of a single, high-dose VD pill. At various times, tumors were harvested and serum was collected to measure levels of VD metabolic intermediates. A significant increase in PpIX levels and in the expression of differentiation and proliferation markers in tumor tissue was observed after VD supplementation of both the deficient and 1K mice. Further results describing mechanistic details of PpIX enhancement through alteration of heme- and VD-metabolic enzyme levels will be presented. Based on these results, a clinical study using oral vitamin D prior to PDT for human skin cancer should be performed.

Real-Time Dosimetry and Optimization of Prostate Photodynamic Therapy

DTIC Science & Technology

2006-09-01

photodynamic therapy in patients with prostate cancer,” IPA 9th World Congress of Photodynamic Medicine, (2003). 2. Zhu TC, Diana S, Dimofte A...photodynamic therapy,” IPA 9th World Congress of Photodynamic Medicine, (2003). 3. Zhu TC, Altschuler M, Xiao Y, Finlay J, Dimofte A, Hahn SM, “Light...Optimization of treatment plan using Cimmino algorithm in prostate photodynamic therapy,” IPA 10th World Congress of Photodynamic Medicine, Munich

Fullerene C60 and graphene photosensibiles for photodynamic virus inactivation

NASA Astrophysics Data System (ADS)

Belousova, I.; Hvorostovsky, A.; Kiselev, V.; Zarubaev, V.; Kiselev, O.; Piotrovsky, L.; Anfimov, P.; Krisko, T.; Muraviova, T.; Rylkov, V.; Starodubzev, A.; Sirotkin, A.; Grishkanich, A.; Kudashev, I.; Kancer, A.; Kustikova, M.; Bykovskaya, E.; Mayurova, A.; Stupnikov, A.; Ruzankina, J.; Afanasyev, M.; Lukyanov, N.; Redka, D.; Paklinov, N.

2018-02-01

A solid-phase photosensitizer based on aggregated C60 fullerene and graphene oxide for photodynamic inactivation of pathogens in biological fluids was studied. The most promising technologies of inactivation include the photodynamic effect, which consists in the inactivation of infectious agents by active oxygen forms (including singlet oxygen), formed when light is activated by the photosensitizer introduced into the plasma. Research shows features of solid-phase systems based on graphene and fullerene C60 oxide, which is a combination of an effective inactivating pathogens (for example, influenza viruses) reactive oxygen species formed upon irradiation of the photosensitizer in aqueous and biological fluids, a high photostability fullerene coatings and the possibility of full recovery photosensitizer from the biological environment after the photodynamic action.

Peptide-based pharmacomodulation of a cancer-targeted optical imaging and photodynamic therapy agent

PubMed Central

Stefflova, Klara; Li, Hui; Chen, Juan; Zheng, Gang

2008-01-01

We designed and synthesized a folate receptor-targeted, water soluble, and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is comprised of three components: 1) Pyropheophorbide a (Pyro) as an imaging and therapeutic agent, 2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and 3) Folate as a homing molecule targeting FR-expressing cancer cells. We observed an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs. HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was observed in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro’s own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe – a process we attributed to a possible peptide-based pharmacomodulation – as was demonstrated by a 50-fold reduction in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted molecular imaging and photodynamic therapy agents. PMID:17298029

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.

Implicit dosimetry of microorganism photodynamic inactivation

NASA Astrophysics Data System (ADS)

Tamošiūnas, Mindaugas; Kuliešienė, Neringa; Daugelavičius, Rimantas

2017-12-01

Photosensitization based antibacterial treatment is efficient against a broad range of pathogens but it utilizes suboptimal dosimetry with an explicit (and very broad range) determination of sensitizer concentration, light dose and fluence rates. In this study we verified the implicit dosimetry approach for pathogen photodynamic treatment, employing protoporphyrin IX (ppIX) photobleaching to assess the killing efficacy against Staphylococcus aureus and Candida albicans cells. The results show that there was an increased kill of S. aureus and C. albicans at higher degree of ppIX fluorescence decay. Therefore ppIX photobleaching can be incorporated into the PDI dose metric offering to predict the pathogen killing efficacy during photodynamic treatment.

Physiological oxygen concentration alters glioma cell malignancy and responsiveness to photodynamic therapy in vitro.

PubMed

Albert, Ina; Hefti, Martin; Luginbuehl, Vera

2014-11-01

The partial pressure of oxygen (pO2) in brain tumors ranges from 5 to 15%. Nevertheless, the majority of in vitro experiments with glioblastoma multiforme (GBM) cell lines are carried out under an atmospheric pO2 of 19 to 21%. Recently, 5-aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), has been introduced to neurosurgery to allow for photodynamic diagnosis and photodynamic therapy (PDT) in high-grade gliomas. Here, we investigate whether low pO2 affects GBM cell physiology, PpIX accumulation, or PDT efficacy. GBM cell lines (U-87 MG and U-251 MG) were cultured under atmospheric (pO2  =  19%) and physiological (pO2  =  9%) oxygen concentrations. PpIX accumulation and localization were investigated, and cell survival and cell death were observed following in vitro PDT. A physiological pO2 of 9% stimulated GBM cell migration, increased hypoxia-inducible factor (HIF)-1 alpha levels, and elevated resistance to camptothecin in U-87 MG cells compared to cultivation at a pO2 of 19%. This oxygen reduction did not alter 5-ALA-induced intracellular PpIX accumulation. However, physiological pO2 changed the responsiveness of U-87 MG but not of U-251 MG cells to in vitro PDT. Around 20% more irradiation light was required to kill U-87 MG cells at physiological pO2, resulting in reduced lactate dehydrogenase (LDH) release (one- to two-fold) and inhibition of caspase 3 activation. Reduction of oxygen concentration from atmospheric to a more physiological level can influence the malignant behavior and survival of GBM cell lines after in vitro PDT. Therefore, precise oxygen concentration control should be considered when designing and performing experiments with GBM cells.

Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature.

PubMed

Rink, Michael; Babjuk, Marko; Catto, James W F; Jichlinski, Patrice; Shariat, Shahrokh F; Stenzl, Arnulf; Stepp, Herbert; Zaak, Dirk; Witjes, J Alfred

2013-10-01

Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required. Copyright © 2013 European Association of

Improving contrast enhancement in magnetic resonance imaging using 5-aminolevulinic acid-induced protoporphyrin IX for high-grade gliomas.

PubMed

Yamamoto, Junkoh; Kakeda, Shingo; Yoneda, Tetsuya; Ogura, Shun-Ichiro; Shimajiri, Shohei; Tanaka, Tohru; Korogi, Yukunori; Nishizawa, Shigeru

2017-03-01

Magnetic resonance imaging (MRI) with a gadolinium-based contrast agent is the gold standard for high-grade gliomas (HGGs). The compound 5-aminolevulinic acid (5-ALA) undergoes a high rate of cellular uptake, particularly in cancer cells. In addition, fluorescence-guided resection with 5-ALA is widely used for imaging HGGs. 5-ALA is water soluble, while protoporphyrin IX (PpIX) is water insoluble. It was speculated whether converting from 5-ALA to PpIX may relatively increase intracellular water content, and consequently, might enhance the T2 signal intensity in HGG. The aim of the present study was to assess whether 5-ALA-induced PpIX enhances the T2 signal intensity in patients with HGGs. A total of 4 patients who were candidates for HGG surgical treatment were prospectively analyzed with preoperative MRI. Patients received oral doses of 5-ALA (20 mg/kg) 3 h prior to anesthesia. At 2.5 h post-5-ALA administration, T2-weighted images (T2WIs) were obtained from all patients. Subsequently, tumors were evaluated via fluorescence using a modified operating microscope. Fluorescent tumor tissues were obtained to analyze the accumulation of 5-ALA-induced PpIX within the tumors, which was confirmed quantitatively by high-performance liquid chromatography (HPLC) analysis. The MRI T2 signal intensity within the tumors was evaluated prior to and following 5-ALA administration. Three glioblastoma multiformes (GBMs) and 1 anaplastic oligodendroglioma (AO) were included in the analysis. Intraoperatively, all GBMs exhibited strong fluorescence of 5-ALA-induced PpIX, whilst no fluorescence was observed in the AO sample. HPLC analysis indicated a higher accumulation of 5-ALA-induced PpIX in the GBM samples compared with the AO sample. In total, 48 regions of interest were identified within the tumors from T2-WIs. In the GBM group, the relative T2 signal intensity value within the tumors following 5-ALA administration was significantly increased compared with the T2 signal

[Photodynamic therapy of dysplasias and early carcinomas in Barrett esophagus with a diode laser system--a pilot study].

PubMed

Zöpf, T; Rosenbaum, A; Apel, D; Jakobs, R; Arnold, J C; Riemann, J F

2001-04-15

Photodynamic therapy (PDT) of dysplasia and early cancer of the esophagus could show good results in the potential of ablation. Unfortunately, the existing expensive and temperamental dye laser systems foiled a broad clinical use. In this pilot study, we investigated the feasibility of an inexpensive and maintenance-free diode laser system for PDT of dysplasia and early cancer in Barrett's esophagus. Eight patients with Barrett's esophagus and/or early cancer were treated. As light source we used a diode laser system with a maximum power output of 2 W and a wavelength of 633 +/- 3 nm. One patient was treated initially with Photosan-3, seven patients received 5-aminolevulinic acid. In all patients we could achieve reduction in length and/or histologically proven downgrading. In three quarters of the patients, complete eradication of adenocarcinoma could be attained. Columnar-lined metaplastic epithelium could also be completely eradicated. PDT using a diode laser system is comparably effective in Barrett's esophagus/early cancer as PDT with dye laser systems. PDT is a gentle and effective technique with little side effects.

Visual perception enhancement for detection of cancerous oral tissue by multi-spectral imaging

NASA Astrophysics Data System (ADS)

Wang, Hsiang-Chen; Tsai, Meng-Tsan; Chiang, Chun-Ping

2013-05-01

Color reproduction systems based on the multi-spectral imaging technique (MSI) for both directly estimating reflection spectra and direct visualization of oral tissues using various light sources are proposed. Images from three oral cancer patients were taken as the experimental samples, and spectral differences between pre-cancerous and normal oral mucosal tissues were calculated at three time points during 5-aminolevulinic acid photodynamic therapy (ALA-PDT) to analyze whether they were consistent with disease processes. To check the successful treatment of oral cancer with ALA-PDT, oral cavity images by swept source optical coherence tomography (SS-OCT) are demonstrated. This system can also reproduce images under different light sources. For pre-cancerous detection, the oral images after the second ALA-PDT are assigned as the target samples. By using RGB LEDs with various correlated color temperatures (CCTs) for color difference comparison, the light source with a CCT of about 4500 K was found to have the best ability to enhance the color difference between pre-cancerous and normal oral mucosal tissues in the oral cavity. Compared with the fluorescent lighting commonly used today, the color difference can be improved by 39.2% from 16.5270 to 23.0023. Hence, this light source and spectral analysis increase the efficiency of the medical diagnosis of oral cancer and aid patients in receiving early treatment.

Fluorescence diagnosis of tumor cells in hemangioblastoma cysts with 5-aminolevulinic acid.

PubMed

Utsuki, Satoshi; Oka, Hidehiro; Sato, Kimitoshi; Shimizu, Satoru; Suzuki, Sachio; Fujii, Kiyotaka

2010-01-01

Peritumoral hemangioblastoma cysts are usually composed of fibrous tissue without tumor cells. The authors describe the first case in which fluorescence with 5-aminolevulinic acid (5-ALA) was used to diagnose a hemangioblastoma tumor in a peritumoral cyst wall. A 27-year-old woman with a homogeneous, enhanced nodular lesion in the right hemisphere of the cerebellum underwent surgical treatment. After the nodular lesion was removed, the cyst region was observed with the aid of a semiconductor laser with a peak wavelength of 405 +/- 1 nm, which was powered using a fiberoptic cable. The cyst region was visualized with strong fluorescence, which disappeared after tissue removal. The fluorescent cyst consisted of tumor cells. The authors conclude that fluorescence diagnosis performed using 5-ALA can inform the choice of removing hemangioblastoma cysts.

Adapting biomodulatory strategies for treatment in new contexts: pancreatic and oral cancers (Conference Presentation)

NASA Astrophysics Data System (ADS)

Anbil, Sriram R.; Rizvi, Imran; Khan, Amjad P.; Celli, Jonathan P.; Maytin, Edward V.; Hasan, Tayyaba

2016-03-01

Biomodulation of cancer cell metabolism represents a promising approach to overcome tumor heterogeneity and poor selectivity, which contribute significantly to treatment resistance. To date, several studies have demonstrated that modulation of cell metabolism including the heme synthesis pathway serves as an elegant approach to improve the efficacy of aminolevulinic acid (ALA) based photodynamic therapy (PDT). However, the ability of biomodulation-enhanced PDT to improve outcomes in low resource settings and to address challenges in treating lethal tumors with exogenous photosensitizers remains underexplored. The ability of vitamin D or methotrexate to enhance PDT efficacy in a carcinogen-induced hamster cheek pouch model of oral squamous cell carcinoma and in 3D cell-based models for pancreatic ductal adenocarcinoma is evaluated. Challenges associated with adapting PDT regimens to low resource settings, understanding the effects of biomodulatory agents on the metabolism of cancer cells, and the differential effects of biomodulatory agents on tumor and stromal cells will be discussed.

Induced Protoporphyrin IX Accumulation by the δ-Aminolevulinic Acid in Bacteria and its Potential Use in the Photodynamic Therapy

NASA Astrophysics Data System (ADS)

Brígido-Aparicio, Cyntiha; Ramón-Gallegos, Eva; Arenas-Huertero, Francisco Jesús; Uribe-Hernández, Raúl

2008-08-01

The increasing incident of resistant strains to antibiotic has encouraged the search of new antibacterial treatments, such as the photodynamic therapy. In recent years, photodynamic therapy has demonstrated being a good technology for the treatment of recurrent bacteria infection. PDT presents a hopeful approach to eliminate Gram positive and negative bacteria in immunological compromised patients. This therapy uses a laser in combination with a photosensibilizer in presence of intracellular molecular oxygen. The process generates an effect of phototoxicity in bacterial cells. The aim of this work was to determine the in vitro conditions to accumulate PpIX in effective concentrations in Staphylococcus aureus ATCC25923 and Streptococcus pyogenes, which are responsible of human cutaneous diseases. A cellular suspension of both strains was prepared in TSB to obtain growth in Log-phase, then, the suspensions were adjusted to a final concentration of 2.61×108 cells/mL. The strains were exposed to increasing concentrations from 0 to 160μg/mL of δ-ALA in order to determinate the concentration that induces the biggest accumulation of PpIX. PpIX was measured using the Piomelli method modified for bacteria. The concentration selected was 40 mg/mL of ALA. It was found that in basal concentration of δ-ALA (0 μg/mL) both strains accumulated similar amount of PpIX. In concentrations of 5 mg/mL of δ-ALA it was observed a significant (p<0.001) increment in PpIX concentration. Finally it was realized a kinetic to determinate the optimal accumulation over the time at 0, 5, 10, 15 and 30 min, and 1, 2, 4, 8, 16 and 32 h. It was found that the ideal time for PDT application, in both strains, was 24 h because in smaller times there was not statistically significant difference. The S. aureus ATCC25923 accumulated significantly the biggest concentration of PpIX with regard to S. pyogenes. In conclusion, it was found that the optimal conditions to apply PDT will be to expose both

Photodynamic therapy--aspects of pain management.

PubMed

Fink, Christine; Enk, Alexander; Gholam, Patrick

2015-01-01

Topical photodynamic therapy (PDT) is a highly effective and safe treatment method for actinic keratoses with an excellent cosmetic outcome and is commonly used for the therapy of large areas of photodamaged skin with multiple clinically manifest and subclinical lesions. However, the major drawback of photodynamic therapy is the pain experienced during the treatment that can be intense and sometimes even intolerable for patients, requiring interruption or termination of the process. Several strategies for controlling pain during photodynamic therapy have been studied but few effective methods are currently available. Therefore, this review puts the spotlight on predictors on pain intensity and aspects of pain management during photodynamic therapy. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

Photodynamic effect of curcumin on Vibrio parahaemolyticus.

PubMed

Wu, Juan; Mou, Haijin; Xue, Changhu; Leung, Albert Wingnang; Xu, Chuanshan; Tang, Qing-Juan

2016-09-01

Vibrio parahaemolyticus (V. parahaemolyticus) is currently a major cause of bacterial diarrhoea associated with seafood consumption. The objective of this study was to determine the inactivation effect of curcumin-mediated photodynamic action on V. parahaemolyticus. First of all, V. parahaemolyticus suspended in PBS buffer was irradiated by a visible light from a LED light source with an energy density of 3.6J/cm(2). Colony forming units (CFU) were counted and the viability of V. parahaemolyticus cells was calculated after treatment. Singlet oxygen ((1)O2) production after photodynamic action of curcumin was evaluated using 9,10-Anthracenediyl-bis (methylene) dimalonic acid (ADMA). Bacterial outer membrane protein was extracted and analyzed using electrophoresis SDS-PAGE. DNA and RNA of V. parahaemolyticus were also extracted and analyzed using agarose gel electrophoresis after photodynamic treatment. Finally, the efficacy of photodynamic action of curcumin was preliminarily evaluated in the decontamination of V. parahaemolyticus in oyster. Results showed that the viability of V. parahaemolyticus was significantly decreased to non-detectable levels over 6.5-log reductions with the curcumin concentration of 10 and 20μM. Photodynamic action of curcumin significantly increased the singlet oxygen level with the curcumin concentration of 10μM. Notable damage was found to bacterial outer membrane proteins and genetic materials after photodynamic treatment. Photodynamic action of curcumin reduced the number of V. parahaemolyticus contaminating in oyster to non-detectable level. Our findings demonstrated that photodynamic action of curcumin could be a potentially good method to inactivate Vibrio parahaemolyticus contaminating in oyster. Copyright © 2016 Elsevier B.V. All rights reserved.

Using Fourier transform infrared spectroscopy to evaluate biological effects induced by photodynamic therapy.

PubMed

Lima, Cassio A; Goulart, Viviane P; Correa, Luciana; Zezell, Denise M

2016-07-01

Vibrational spectroscopic methods associated with multivariate statistical techniques have been succeeded in discriminating skin lesions from normal tissues. However, there is no study exploring the potential of these techniques to assess the alterations promoted by photodynamic effect in tissue. The present study aims to demonstrate the ability of Fourier Transform Infrared (FTIR) spectroscopy on Attenuated total reflection (ATR) sampling mode associated with principal component-linear discriminant analysis (PC-LDA) to evaluate the biochemical changes caused by photodynamic therapy (PDT) in skin neoplastic tissue. Cutaneous neoplastic lesions, precursors of squamous cell carcinoma (SCC), were chemically induced in Swiss mice and submitted to a single session of 5-aminolevulinic acid (ALA)-mediated PDT. Tissue sections with 5 μm thickness were obtained from formalin-fixed paraffin-embedded (FFPE) and processed prior to the histopathological analysis and spectroscopic measurements. Spectra were collected in mid-infrared region using a FTIR spectrometer on ATR sampling mode. Principal Component-Linear Discriminant Analysis (PC-LDA) was applied on preprocessed second derivatives spectra. Biochemical changes were assessed using PCA-loadings and accuracy of classification was obtained from PC-LDA . Sub-bands of Amide I (1,624 and 1,650 cm(-1) ) and Amide II (1,517 cm(-1) ) indicated a protein overexpression in non-treated and post-PDT neoplastic tissue compared with healthy skin, as well as a decrease in collagen fibers (1,204, 1,236, 1,282, and 1,338 cm(-1) ) and glycogen (1,028, 1,082, and 1,151 cm(-1) ) content. Photosensitized neoplastic tissue revealed shifted peak position and decreased β-sheet secondary structure of proteins (1,624 cm(-1) ) amount in comparison to non-treated neoplastic lesions. PC-LDA score plots discriminated non-treated neoplastic skin spectra from post-PDT cutaneous lesions with accuracy of 92.8%, whereas non-treated neoplastic

Spectrophotometric photodynamic detection involving extracorporeal treatment with hexaminolevulinate for bladder cancer cells in voided urine.

PubMed

Nakai, Yasushi; Ozawa, Toshiyuki; Mizuno, Fumiko; Onishi, Sayuri; Owari, Takuya; Hori, Syunta; Morizawa, Yosuke; Tatsumi, Yosihiro; Miyake, Makito; Tanaka, Nobumichi; Tsuruta, Daisuke; Fujimoto, Kiyohide

2017-11-01

To evaluate the feasibility of hexaminolevulinate (HAL) for the photodynamic detection of cancer cells in voided urine. This study included 50 patients with bladder cancer that was confirmed histologically after transurethral resection (bladder cancer group) and 50 outpatients without a history of urothelial carcinoma or cancer-related findings (no malignancy group). One third of the voided urine samples were incubated with aminolevulinic acid (ALA-treated samples), one third were incubated with HAL (HAL-treated samples), and the remaining samples were incubated without treatment (untreated samples). For detecting cellular protoporphyrin IX levels, the intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated or HAL-treated samples and the untreated samples at 635 nm was calculated. HAL-induced fluorescence cytology (HFC) showed that the difference was significantly higher in patients with high-grade tumors than in those with low-grade tumors (p = 0.0003) and the difference was significantly higher in patients with low-grade tumors than in those without a history of urothelial carcinoma or cancer-related findings (p = 0.021). The areas under the receiver operating characteristic curves of ALA-induced fluorescence cytology (AFC) and HFC were 0.77 and 0.81, respectively. The AUC of HFC was significantly higher than that of AFC (p < 0.0001). The overall sensitivity values for conventional cytology, AFC, and HFC were 49, 74, and 74%, respectively. The overall specificity values for AFC and HFC were 70 and 94%, respectively. Spectrophotometric photodynamic detection involving extracorporeal treatment with HAL for bladder cancer cells in voided urine showed high accuracy. This bladder cancer detection method is easy and cost-effective, and has the potential for clinical use.

Photodynamic diagnosis in upper urinary tract urothelial carcinoma: A systematic review.

PubMed

Osman, Elsawi; Alnaib, Ziad; Kumar, Nitya

2017-06-01

To assess the diagnostic accuracy and safety of photodynamic diagnosis (PDD) in upper urinary tract urothelial carcinoma (UUTUC). A systematic literature search was conducted. Included studies were assessed for the risks of bias and quality using appropriate tools. Dedicated data extraction forms were used. Diagnostic accuracy in terms of sensitivity and specificity were quoted whenever provided by individual studies. A combined toxicity profile of 5-aminolevulinic acid (5ALA) was given after reviewing individual studies. In all, 17 studies were identified. After screening seven studies were included involving a total of 194 patients. None of the studies were randomised. All the available studies were of low-to-moderate quality. The largest available study, with 106 patients, reported a sensitivity of 95.8% and 53.5% for PDD and white-light (WL) ureterorenoscopy (URS) respectively, with a statistically significant difference. The specificity was 96.6% for PDD and 95.2% for WL-URS with no statistical significance. PDD showed better ability in detecting carcinoma in situ and dysplasia. One study compared PDD to computed tomography urogram (CTU) and found PDD to have better sensitivity and statistically significantly better specificity. 5ALA-associated toxicity was minor in nature and hypotension was the most common adverse event. PDD in UUTUC appears to be more accurate than WL-URS and CTU, with no significant toxicity. Larger scale randomised trials are needed.

Lysosomal Signaling Enhances Mitochondria-Mediated Photodynamic Therapy in A431 Cancer Cells: Role of Iron

PubMed Central

Saggu, Shalini; Hung, Hsin-I; Quiogue, Geraldine; Lemasters, John J.; Nieminen, Anna-Liisa

2015-01-01

In photodynamic therapy (PDT), light activates a photosensitizer added to a tissue, resulting in singlet oxygen formation and cell death. The photosensitizer phthalocyanine 4 (Pc 4) localizes primarily to mitochondrial membranes in cancer cells, resulting in mitochondria-mediated cell death. The aim of this study was to determine how lysosomes contribute to PDT-induced cell killing by mitochondria-targeted photosensitizers such as Pc 4. We monitored cell killing of A431 cells after Pc 4-PDT in the presence and absence of bafilomycin, an inhibitor of the vacuolar proton pump of lysosomes and endosomes. Bafilomycin was not toxic by itself, but greatly enhanced Pc 4-PDT-induced cell killing. To investigate whether iron loading of lysosomes affects bafilomycin-induced killing, cells were incubated with ammonium ferric citrate (30 μm) for 30 h prior to PDT. Ammonium ferric citrate enhanced Pc 4 plus bafilomycin-induced cell killing without having toxicity by itself. Iron chelators (desferrioxamine and starch-desferrioxamine) and the inhibitor of the mitochondrial calcium (and ferrous iron) uniporter, Ru360, protected against Pc 4 plus bafilomycin toxicity. These results support the conclusion that chelatable iron stored in the lysosomes enhances the efficacy of bafilomycin-mediated PDT and that lysosomal disruption augments PDT with Pc 4. PMID:22220628

Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis

NASA Astrophysics Data System (ADS)

Kanick, Stephen Chad; Davis, Scott C.; Zhao, Yan; Hasan, Tayyaba; Maytin, Edward V.; Pogue, Brian W.; Chapman, M. Shane

2014-07-01

Dosimetry for aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy of actinic keratosis was examined with an optimized fluorescence dosimeter to measure PpIX during treatment. While insufficient PpIX generation may be an indicator of incomplete response, there exists no standardized method to quantitate PpIX production at depths in the skin during clinical treatments. In this study, a spectrometer-based point probe dosimeter system was used to sample PpIX fluorescence from superficial (blue wavelength excitation) and deeper (red wavelength excitation) tissue layers. Broadband white light spectroscopy (WLS) was used to monitor aspects of vascular physiology and inform a correction of fluorescence for the background optical properties. Measurements in tissue phantoms showed accurate recovery of blood volume fraction and reduced scattering coefficient from WLS, and a linear response of PpIX fluorescence versus concentration down to 1.95 and 250 nM for blue and red excitations, respectively. A pilot clinical study of 19 patients receiving 1-h ALA incubation before treatment showed high intrinsic variance in PpIX fluorescence with a standard deviation/mean ratio of >0.9. PpIX fluorescence was significantly higher in patients reporting higher pain levels on a visual analog scale. These pilot data suggest that patient-specific PpIX quantitation may predict outcome response.

DNA Duplex-Based Photodynamic Molecular Beacon for Targeted Killing of Retinoblastoma Cell.

PubMed

Wei, Yanchun; Lu, Cuixia; Chen, Qun; Xing, Da

2016-11-01

Retinoblastoma (RB) is the most common primary intraocular malignancy of infancy. An alternative RB treatment protocol is proposed and tested. It is based on a photodynamic therapy (PDT) with a designed molecular beacon that specifically targets the murine double minute x (MDMX) high-expressed RB cells. A MDMX mRNA triggered photodynamic molecular beacon is designed by binding a photosensitizer molecule (pyropheophorbide-a, or PPa) and a black hole quencher-3 (BHQ3) through a complementary oligonucleotide sequence. Cells with and without MDMX high-expression are incubated with the beacon and then irradiated with a laser. The fluorescence and reactive oxygen species are detected in solution to verify the specific activation of PPa by the perfectly matched DNA targets. The cell viabilities are evaluated with CCK-8 and flow cytometry assay. The fluorescence and photo-cytoxicity of PPa is recovered and significantly higher in the MDMX high-expressed Y79 and WERI-Rb1 cells, compared to that with the MDMX low-expressed cells. The synthesized beacon exhibits high PDT efficiency toward MDMX high-expressed RB cells. The data suggest that the designed beacon may provide a potential alternative for RB therapy and secures the ground for future investigation.

A new therapeutic proposal for inoperable osteosarcoma: Photodynamic therapy.

PubMed

de Miguel, Guilherme Chohfi; Abrantes, Ana Margarida; Laranjo, Mafalda; Grizotto, Ana Yoshie Kitagawa; Camporeze, Bruno; Pereira, José Aires; Brites, Gonçalo; Serra, Arménio; Pineiro, Marta; Rocha-Gonsalves, António; Botelho, Maria Filomena; Priolli, Denise Gonçalves

2018-03-01

Osteosarcoma, a malignant tumor characterized by bone or osteoid formation, is the second most common primary bone neoplasm. Clinical symptoms include local and surrounding pain, unrelieved by rest or anesthesia. Osteosarcoma has a poor chemotherapeutic response with prognosis dependent on complete tumor excision. Therefore, for inoperable osteosarcoma new therapeutic strategies are needed. The present study aimed to develop murine models of cranial and vertebral osteosarcoma that facilitate simple clinical monitoring and real-time imaging to evaluate the outcome of photodynamic therapy based on a previously developed photosensitizer. Balb/c nude mice were divided into two groups: the cranial and vertebral osteosarcoma groups. Each group was further subdivided into the photodynamic therapy-treated and untreated groups. Images were obtained by scintigraphy with 99m Tc-MIBI and radiography. Tumor growth, necrotic area, osteoid matrix area, and inflammatory infiltration were analyzed. Cranial and vertebral tumors could be macroscopically observed and measured. Radiographic and scintigraphic images showed tumor cells present at the inoculation sites. After photodynamic therapy, scintigraphy showed lower tumoral radiopharmaceutical uptake, which correlated histologically with increased necrosis. Osteoid matrix volume increased, and tumor size decreased in all photodynamic therapy-treated animals. Cranial and vertebral osteosarcoma models in athymic mice are feasible and facilitate in vivo monitoring for the development of new therapies. Photodynamic therapy is a potential antitumoral treatment for surgically inoperable osteosarcoma. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Evaluation of Hydrogel Suppositories for Delivery of 5-Aminolevulinic Acid and Hematoporphyrin Monomethyl Ether to Rectal Tumors.

PubMed

Ye, Xuying; Yin, Huijuan; Lu, Yu; Zhang, Haixia; Wang, Han

2016-10-12

We evaluated the potential utility of hydrogels for delivery of the photosensitizing agents 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) to rectal tumors. Hydrogel suppositories containing ALA or HMME were administered to the rectal cavity of BALB/c mice bearing subcutaneous tumors of SW837 rectal carcinoma cells. For comparison, ALA and HMME were also administered by three common photosensitizer delivery routes; local administration to the skin and intratumoral or intravenous injection. The concentration of ALA-induced protoporphyrin IX or HMME in the rectal wall, skin, and subcutaneous tumor was measured by fluorescence spectrophotometry, and their distribution in vertical sections of the tumor was measured using a fluorescence spectroscopy system. The concentration of ALA-induced protoporphyrin IX in the rectal wall after local administration of suppositories to the rectal cavity was 9.76-fold (1 h) and 5.8-fold (3 h) higher than in the skin after cutaneous administration. The maximal depth of ALA penetration in the tumor was ~3-6 mm at 2 h after cutaneous administration. Much lower levels of HMME were observed in the rectal wall after administration as a hydrogel suppository, and the maximal depth of tumor penetration was <2 mm after cutaneous administration. These data show that ALA more readily penetrates the mucosal barrier than the skin. Administration of ALA as an intrarectal hydrogel suppository is thus a potential delivery route for photodynamic therapy of rectal cancer.

Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery: A Histology-Based Evaluation.

PubMed

Hauser, Sonja B; Kockro, Ralf A; Actor, Bertrand; Sarnthein, Johannes; Bernays, René-Ludwig

2016-04-01

Glioblastoma resection guided by 5-aminolevulinic acid (5-ALA) fluorescence and intraoperative magnetic resonance imaging (iMRI) may improve surgical results and prolong survival. To evaluate 5-ALA fluorescence combined with subsequent low-field iMRI for resection control in glioblastoma surgery. Fourteen patients with suspected glioblastoma suitable for complete resection of contrast-enhancing portions were enrolled. The surgery was carried out using 5-ALA-induced fluorescence and frameless navigation. Areas suspicious for tumor underwent biopsy. After complete resection of fluorescent tissue, low-field iMRI was performed. Areas suspicious for tumor remnant underwent biopsy under navigation guidance and were resected. The histological analysis was blinded. In 13 of 14 cases, the diagnosis was glioblastoma multiforme. One lymphoma and 1 case without fluorescence were excluded. In 11 of 12 operations, residual contrast enhancement on iMRI was found after complete resection of 5-ALA fluorescent tissue. In 1 case, the iMRI enhancement was in an eloquent area and did not undergo a biopsy. The 28 biopsies of areas suspicious for tumor on iMRI in the remaining 10 cases showed tumor in 39.3%, infiltration zone in 25%, reactive central nervous system tissue in 32.1%, and normal brain in 3.6%. Ninety-three fluorescent and 24 non-fluorescent tissue samples collected before iMRI contained tumor in 95.7% and 87.5%, respectively. 5-ALA fluorescence-guided resection may leave some glioblastoma tissue undetected. MRI might detect areas suspicious for tumor even after complete resection of all fluorescent tissue; however, due to the limited accuracy of iMRI in predicting tumor remnant (64.3%), resection of this tissue has to be considered with caution in eloquent regions.

Formation of Mg-Containing Chlorophyll Precursors from Protoporphyrin IX, δ-Aminolevulinic Acid, and Glutamate in Isolated, Photosynthetically Competent, Developing Chloroplasts 1

PubMed Central

Fufsler, Thomas P.; Castelfranco, Paul A.; Wong, Yum-Shing

1984-01-01

Intact developing chloroplasts isolated from greening cucumber (Cucumis sativus L. var Beit Alpha) cotyledons were found to contain all the enzymes necessary for the synthesis of chlorophyllide. Glutamate was converted to Mg-protoporphyrin IX (monomethyl ester) and protoclorophyllide. δ-Aminolevulinic acid and protoporphyrin IX were converted to Mg-protoporphyrin IX, Mg-protoporphyrin IX monomethyl ester, protochlorophyllide and chlorophyllide a. The conversion of δ-aminolevulinic acid or protoporphyrin IX to Mg-protoporphyrin IX (monomethyl ester) was inhibited by AMP and p-chloromercuribenzene sulfonate. Light stimulated the formation of Mg-protoporphyrin IX from all three substrates. In the case of δ-aminolevulinic acid and protoporphyrin IX, light could be replaced by exogenous ATP. In the case of glutamate, both ATP and reducing power were necessary to replace light. With all three substrates, glutamate, δ-aminolevulinic acid, and protoporphyrin IX, the stimulation of Mg-protoporphyrin IX accumulation in the light was abolished by DCMU, and this DCMU block was overcome by added ATP and reducing power. PMID:16663535

In-vivo luminescence model for the study of tumor regression and regrowth following combination regimens with differentiation-promoting agents and photodynamic therapy

NASA Astrophysics Data System (ADS)

Rollakanti, K.; Anand, S.; Maytin, E. V.

2013-03-01

Photodynamic therapy with aminolevulinic acid can be modified by pretreatment regimens with drugs such as 5- Fluorouracil (5-FU) or Vitamin D (calcitriol) that enhance accumulation of protoporphyrin IX (PpIX) within tumor tissue which presumably will enhance the therapeutic response to light. However, histological approaches for monitoring therapeutic responses are poorly suited for studying long term survival because large numbers of mice need to be sacrificed. To address this limitation, a non-invasive model to monitor tumor regression and regrowth has been established. Breast cancer cells, stably transfected with firefly luciferase (MDA-Luc cell line), are implanted orthotopically in nude mice (0.25 - 1 x 106 cells/site), and monitored 0-60 min after s.c. injection of luciferin, with Xenogen in-vivo imaging system. Luminescence is detectable at day 1 post-implantation. Tumors are suitable for experimentation on day 6, when daily injections of pretreatment agents (5-FU, 300 mg/kg; calcitriol, 1 μg/kg) begin. On day 9, ALA (75 mg/kg i.p.) is given for 4 hr, followed by illumination (633 nm, 100 J/cm2). Tumor luminescence post- PDT is monitored daily and compared with caliper measurements. Pretreatments (5-FU, calcitriol) by themselves do not inhibit luciferase expression, and all tumors grow at a similar rate during the pretreatment period. Results from in vivo survival experiments can be correlated to survival responses of MDA-Luc cells grown in monolayer cultures +/- PDT and +/- pretreatments, and additional mechanistic information (e.g. Ki67 and E-cadherin expression) obtained. In summary, this noninvasive model will permit testing of the therapeutic survival advantages of various pretreatments during cPDT.

Enhanced plasmonic resonance energy transfer in mesoporous silica-encased gold nanorod for two-photon-activated photodynamic therapy.

PubMed

Chen, Nai-Tzu; Tang, Kuo-Chun; Chung, Ming-Fang; Cheng, Shih-Hsun; Huang, Ching-Mao; Chu, Chia-Hui; Chou, Pi-Tai; Souris, Jeffrey S; Chen, Chin-Tu; Mou, Chung-Yuan; Lo, Leu-Wei

2014-01-01

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer.

Fractional laser-assisted delivery of methyl aminolevulinate: Impact of laser channel depth and incubation time.

PubMed

Haak, Christina S; Farinelli, William A; Tam, Joshua; Doukas, Apostolos G; Anderson, R Rox; Haedersdal, Merete

2012-12-01

Pretreatment of skin with ablative fractional lasers (AFXL) enhances the uptake of topical photosensitizers used in photodynamic therapy (PDT). Distribution of photosensitizer into skin layers may depend on depth of laser channels and incubation time. This study evaluates whether depth of intradermal laser channels and incubation time may affect AFXL-assisted delivery of methyl aminolevulinate (MAL). Yorkshire swine were treated with CO2 AFXL at energy levels of 37, 190, and 380 mJ/laser channel and subsequent application of MAL cream (Metvix) for 30, 60, 120, and 180 minutes incubation time. Fluorescence photography and fluorescence microscopy quantified MAL-induced porphyrin fluorescence (PpIX) at the skin surface and at five specific skin depths (120, 500, 1,000, 1,500, and 1,800 µm). Laser channels penetrated into superficial (∼300 µm), mid (∼1,400 µm), and deep dermis/upper subcutaneous fat layer (∼2,100 µm). Similar fluorescence intensities were induced at the skin surface and throughout skin layers independent of laser channel depth (180 minutes; P < 0.19). AFXL accelerated PpIX fluorescence from skin surface to deep dermis. After laser exposure and 60 minutes MAL incubation, surface fluorescence was significantly higher compared to intact, not laser-exposed skin at 180 minutes (AFXL-MAL 60 minutes vs. MAL 180 minutes, 69.16 a.u. vs. 23.49 a.u.; P < 0.01). Through all skin layers (120-1,800 µm), laser exposure and 120 minutes MAL incubation induced significantly higher fluorescence intensities in HF and dermis than non-laser exposed sites at 180 minutes (1,800 µm, AFXL-MAL 120 minutes vs. MAL 180 minutes, HF 14.76 a.u. vs. 6.69 a.u. and dermis 6.98 a.u. vs. 5.87 a.u.; P < 0.01). AFXL pretreatment accelerates PpIX accumulation, but intradermal depth of laser channels does not affect porphyrin accumulation. Further studies are required to examine these findings in clinical trials. Copyright

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.

Investigation of photodynamic activity of water-soluble porphyrins in vitro and in vivo

NASA Astrophysics Data System (ADS)

Gyulkhandanyan, Grigor V.; Ghambaryan, Sona S.; Amelyan, Gayane V.; Ghazaryan, Robert K.; Arsenyan, Flora H.; Gyulkhandanyan, Aram G.

2006-02-01

Photodynamic therapy (PDT) is the method of photosensitized tumor treatment. It is based on the photosensitizer (PS) selective accumulation in tumors, its subsequent activation under the light influence and oxygen active form formation that results in tumor destruction. Photodynamic action of some new water-soluble porphyrins was investigated in our laboratory. Dose-dependent effect of these porphyrins was shown on PC-12 murine pheochromocytoma cell line. The results revealed that the efficiency of the investigated porphyrins decreased in the following way: TOEPyP (meso-tetra-(4-N-oxyethylpyridyl)porphyrin) > Zn-TOEPyP > Ag-TOEPyP. It was shown that TOEPyP possessed nearly the same photodynamic activity (LD50) as well-known photosensitizer chlorin e6. These porphyrins have also demonstrated quite high photodynamic activity in vivo. The results were obtained in the experiments on white mice with engrafted C-180 (Croker's sarcoma). Antitumor activity of these porphyrins in the dark was 30-40%, whereas photodynamic activity was 45-60%.

Topical photodynamic therapy of squamous cell carcinomas in a hairless mouse model

NASA Astrophysics Data System (ADS)

Wang, Hong-Wei; Lv, Ting; Li, Jing-Jing; Tu, Qingfeng; Huang, Zheng; Wang, Xiu-Li

2013-02-01

Objectives: To examine therapeutic effects of 5-aminolevulinate (ALA)-mediated photodynamic therapy (PDT) on UVB-induced cutaneous squamous cell carcinomas (SCCs) in a mouse model. Materials and methods: Cutaneous SCCs were established by UVB (280-320 nm) irradiation of hairless mice. In situ fluorescence measurement was used to monitor PpIX formation after the topical application of various concentrations of ALA cream to determine the optimal ALA dose. Therapeutic responses of SCCs to multiple sessions of ALA PDT were examined histologically and quantitatively. TUNEL staining was used to examine apoptosis caused by PDT. Results: After repeated exposure for 18 to 22 weeks (4-5 days/week), multiple nodular and verrucous hyperplasia lesions of various sizes developed at the exposed area. After four sessions of ALA PDT (8% ALA, 3 h incubation, 30 J/cm2 at 20 mW/cm2) a total of 84% of complete response was achieved for small SCCs (1-4 mm, thickness <2.5 mm). TUNEL staining showed that PDT-induced apoptotic cells were distributed evenly from the basal to stratum corneum layers. Conclusions: Topical ALA PDT can trigger apoptosis in SCCs, inhibit SCC growth, and reduce the size and number of tumors in the hairless mouse model. The true clinical value of ALA PDT for the treatment of cutaneous SCC deserves further investigation.

Hypocrellin B and nano silver loaded polymeric nanoparticles: Enhanced generation of singlet oxygen for improved photodynamic therapy.

PubMed

Natesan, Subramanian; Krishnaswami, Venkateshwaran; Ponnusamy, Chandrasekar; Madiyalakan, Madi; Woo, Thomas; Palanisamy, Rajaguru

2017-08-01

A nanoparticulate photodynamic approach was employed with an objective to achieve enhanced production of singlet oxygen ( 1 O 2 ), for the management of posterior segment eye diseases like age related macular degeneration. The hypocrellin B (HB) loaded poly lactide-co-glycolide nanoparticle formulations were incorporated with nano silver (HBS-NPs). The optimized HBS-NPs contained 2.60±0.06mg/mL of HB and showed (i) 135.6 to 828.2nm size range, and (ii) negative zeta potential with a narrow polydispersity index. The DSC thermograms suggested the amorphous nature of HB inside the HBS-NPs. With the average encapsulation efficiency of 92.9±1.79%, the drug release from the HBS-NPs followed a biphasic pattern with an initial burst of 3.50% during first 8h followed by a sustained release of 47.82% within 3days. The interaction between nano silver and HB as assessed by the increase in spectral intensity of Raman spectrum demonstrates that HB may be attached over the nano silver. Generation of reactive oxygen species (ROS) by HBS-NPs was significantly higher than that of HB/HB-NPs. The singlet oxygen generating efficiency assessed using EPR spectrometer follows the order of nano silver>HB-NPs>pure HB drug solution>HBS-NPs. The HBS-NPs had a concentration and time dependent phototoxicity on A549 (human adeno lung carcinoma) cells in the presence of light providing a superior phototoxic effect (82.2% at 50μM) at 2h irradiation. The CAM treated with HBS-NPs showed a significant anti-angiogenic effect compared to a blank formulation. In vivo biodistribution studies revealed that intravenous administration of HBS-NPs lead into significant exposure to the posterior segment of the eye. This proof of principle study demonstrates that HB based nanoparticles may be a valuable new tool for application in ocular photodynamic therapy for the treatment of AMD in future. Copyright © 2017 Elsevier B.V. All rights reserved.

Availability of tissue rinse liquid-based cytology for the rapid diagnosis of sentinel lymph node metastasis and improved bilateral detection by photodynamic eye camera.

PubMed

Kato, Hidenori; Ohba, Yoko; Yamazaki, Hiroyuki; Minobe, Shin-Ichiro; Sudo, Satoko; Todo, Yukiharu; Okamoto, Kazuhira; Yamashiro, Katsushige

2015-08-01

On sentinel lymph node navigation surgery for early invasive cervical cancers, to gain high sensitivity and specificity, the sentinel nodes should be detected bilaterally and pathological diagnosis should be sensitive to detect micrometastasis. To improve these problems, we tried tissue rinse liquid-based cytology and the photodynamic eye. From 2005 to 2013, 102 patients with Stage Ib1 uterine cervical cancer were subjected to sentinel lymph node navigation surgery with Technetium-99 m colloid and blue dye. For the recent 11 patients with whom bilateral sentinel node detection was not available, the photodynamic eye was selectively examined. The detected sentinel node was cut along the minor axis into 2 mm slices, soaked in 10 ml CytoRich red and then subjected to tissue rinse liquid-based cytology at the time of surgery. With the accumulation of 102 Ib1 patients subjected to sentinel lymph node navigation surgery, the bilateral sentinel node detection rate was 67.7%. The photodynamic eye was examined for the recent 11 patients who did not have bilateral signals. Out of the 11, 10 patients obtained bilateral signals successfully. During the period of examining the photodynamic eye, a total of 34 patients were subjected to sentinel lymph node navigation surgery. Thus, the overall bilateral detection rate increased to 97% in this subset. Two hundred and five lymph nodes were available as sentinel nodes. The sensitivity of tissue rinse liquid-based cytology was 91.7%, and the specificity was 100%. False positivity was 0% and false negativity was 8.3%. Detection failure was observed only with one micrometastasis and one case of isolated tumor cells. Combination of photodynamic eye detection and tissue rinse liquid-based cytology pathology can be a promising method for more rewarding sentinel node detection. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Low-cost photodynamic therapy devices for global health settings: Characterization of battery-powered LED performance and smartphone imaging in 3D tumor models

NASA Astrophysics Data System (ADS)

Hempstead, Joshua; Jones, Dustin P.; Ziouche, Abdelali; Cramer, Gwendolyn M.; Rizvi, Imran; Arnason, Stephen; Hasan, Tayyaba; Celli, Jonathan P.

2015-05-01

A lack of access to effective cancer therapeutics in resource-limited settings is implicated in global cancer health disparities between developed and developing countries. Photodynamic therapy (PDT) is a light-based treatment modality that has exhibited safety and efficacy in the clinic using wavelengths and irradiances achievable with light-emitting diodes (LEDs) operated on battery power. Here we assess low-cost enabling technology to extend the clinical benefit of PDT to regions with little or no access to electricity or medical infrastructure. We demonstrate the efficacy of a device based on a 635 nm high-output LED powered by three AA disposable alkaline batteries, to achieve strong cytotoxic response in monolayer and 3D cultures of A431 squamous carcinoma cells following photosensitization by administering aminolevulinic acid (ALA) to induce the accumulation of protoporphyrin IX (PpIX). Here we characterize challenges of battery-operated device performance, including battery drain and voltage stability specifically over relevant PDT dose parameters. Further motivated by the well-established capacity of PDT photosensitizers to serve as tumour-selective fluorescence contrast agents, we demonstrate the capability of a consumer smartphone with low-cost add-ons to measure concentration-dependent PpIX fluorescence. This study lays the groundwork for the on-going development of image-guided ALA-PDT treatment technologies for global health applications.

Low-cost photodynamic therapy devices for global health settings: Characterization of battery-powered LED performance and smartphone imaging in 3D tumor models

PubMed Central

Hempstead, Joshua; Jones, Dustin P.; Ziouche, Abdelali; Cramer, Gwendolyn M.; Rizvi, Imran; Arnason, Stephen; Hasan, Tayyaba; Celli, Jonathan P.

2015-01-01

A lack of access to effective cancer therapeutics in resource-limited settings is implicated in global cancer health disparities between developed and developing countries. Photodynamic therapy (PDT) is a light-based treatment modality that has exhibited safety and efficacy in the clinic using wavelengths and irradiances achievable with light-emitting diodes (LEDs) operated on battery power. Here we assess low-cost enabling technology to extend the clinical benefit of PDT to regions with little or no access to electricity or medical infrastructure. We demonstrate the efficacy of a device based on a 635 nm high-output LED powered by three AA disposable alkaline batteries, to achieve strong cytotoxic response in monolayer and 3D cultures of A431 squamous carcinoma cells following photosensitization by administering aminolevulinic acid (ALA) to induce the accumulation of protoporphyrin IX (PpIX). Here we characterize challenges of battery-operated device performance, including battery drain and voltage stability specifically over relevant PDT dose parameters. Further motivated by the well-established capacity of PDT photosensitizers to serve as tumour-selective fluorescence contrast agents, we demonstrate the capability of a consumer smartphone with low-cost add-ons to measure concentration-dependent PpIX fluorescence. This study lays the groundwork for the on-going development of image-guided ALA-PDT treatment technologies for global health applications. PMID:25965295

Low-cost photodynamic therapy devices for global health settings: Characterization of battery-powered LED performance and smartphone imaging in 3D tumor models.

PubMed

Hempstead, Joshua; Jones, Dustin P; Ziouche, Abdelali; Cramer, Gwendolyn M; Rizvi, Imran; Arnason, Stephen; Hasan, Tayyaba; Celli, Jonathan P

2015-05-12

A lack of access to effective cancer therapeutics in resource-limited settings is implicated in global cancer health disparities between developed and developing countries. Photodynamic therapy (PDT) is a light-based treatment modality that has exhibited safety and efficacy in the clinic using wavelengths and irradiances achievable with light-emitting diodes (LEDs) operated on battery power. Here we assess low-cost enabling technology to extend the clinical benefit of PDT to regions with little or no access to electricity or medical infrastructure. We demonstrate the efficacy of a device based on a 635 nm high-output LED powered by three AA disposable alkaline batteries, to achieve strong cytotoxic response in monolayer and 3D cultures of A431 squamous carcinoma cells following photosensitization by administering aminolevulinic acid (ALA) to induce the accumulation of protoporphyrin IX (PpIX). Here we characterize challenges of battery-operated device performance, including battery drain and voltage stability specifically over relevant PDT dose parameters. Further motivated by the well-established capacity of PDT photosensitizers to serve as tumour-selective fluorescence contrast agents, we demonstrate the capability of a consumer smartphone with low-cost add-ons to measure concentration-dependent PpIX fluorescence. This study lays the groundwork for the on-going development of image-guided ALA-PDT treatment technologies for global health applications.

Reduction of thermal damage in photodynamic therapy by laser irradiation techniques.

PubMed

Lim, Hyun Soo

2012-12-01

General application of continuous-wave (CW) laser irradiation modes in photodynamic therapy can cause thermal damage to normal tissues in addition to tumors. A new photodynamic laser therapy system using a pulse irradiation mode was optimized to reduce nonspecific thermal damage. In in vitro tissue specimens, tissue energy deposition rates were measured in three irradiation modes, CW, pulse, and burst-pulse. In addition, methods were tested for reducing variations in laser output and specific wavelength shifts using a thermoelectric cooler and thermistor. The average temperature elevation per 10 J/cm2 was 0.27°C, 0.09°C, and 0.08°C using the three methods, respectively, in pig muscle tissue. Variations in laser output were controlled within ± 0.2%, and specific wavelength shift was limited to ± 3 nm. Thus, optimization of a photodynamic laser system was achieved using a new pulse irradiation mode and controlled laser output to reduce potential thermal damage during conventional CW-based photodynamic therapy.

Bacteriostatic influence of red laser light on the growth of Staphylococcus aureus and photodynamic enhancement of this effect with Photoditazine

NASA Astrophysics Data System (ADS)

Egorova, A. V.; Brill, G. E.; Bugaeva, I. O.; Tuchina, E. S.; Ponomaryov, G. V.; Ushakova, O. V.

2018-04-01

The influence of red laser irradiation on the growth of colonies of Staphylococcus aureus and photodynamic effect of the photosensitizer Photoditazine were performed. It was established that the emission of red laser light caused an inhibition of bacterial growth. This effect on standard strain of Staphylococcus aureus was evident only when relatively high doses of radiation (180 j/cm2). Photosensitivity of the methicillin-resistant strains was much higher: bacteriostatic effect of red light was observed already at the dose of 60 j/cm2 . Pre-treatment of bacterial cells by Photoditazine significantly enhances the inhibitory effect of the laser light.

New method of acne disease fluorescent diagnostics in natural and fluorescent light and treatment control

NASA Astrophysics Data System (ADS)

Karimova, L. N.; Berezin, A. N.; Shevchik, S. A.; Kharnas, S. S.; Kusmin, S. G.; Loschenov, V. B.

2005-08-01

In the given research the new method of fluorescent diagnostics (FD) and photodynamic therapy (PDT) control of acne disease is submitted. Method is based on simultaneous diagnostics in natural and fluorescent light. PDT was based on using 5-ALA (5- aminolevulinic acid) preparation and 600-730 nanometers radiation. If the examined site of a skin possessed a high endogenous porphyrin fluorescence level, PDT was carried out without 5-ALA. For FD and treatment control a dot spectroscopy and the fluorescent imaging of the affected skin were used.

T-Opt: A 3D Monte Carlo simulation for light delivery design in photodynamic therapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Honda, Norihiro; Hazama, Hisanao; Awazu, Kunio

2017-02-01

The interstitial photodynamic therapy (iPDT) with 5-aminolevulinic acid (5-ALA) is a safe and feasible treatment modality of malignant glioblastoma. In order to cover the tumour volume, the exact position of the light diffusers within the lesion is needed to decide precisely. The aim of this study is the development of evaluation method of treatment volume with 3D Monte Carlo simulation for iPDT using 5-ALA. Monte Carlo simulations of fluence rate were performed using the optical properties of the brain tissue infiltrated by tumor cells and normal tissue. 3-D Monte Carlo simulation was used to calculate the position of the light diffusers within the lesion and light transport. The fluence rate near the diffuser was maximum and decreased exponentially with distance. The simulation can calculate the amount of singlet oxygen generated by PDT. In order to increase the accuracy of simulation results, the parameter for simulation includes the quantum yield of singlet oxygen generation, the accumulated concentration of photosensitizer within tissue, fluence rate, molar extinction coefficient at the wavelength of excitation light. The simulation is useful for evaluation of treatment region of iPDT with 5-ALA.

5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review.

PubMed

Guyotat, Jacques; Pallud, Johan; Armoiry, Xavier; Pavlov, Vladislav; Metellus, Philippe

2016-01-01

The current first-line treatment of malignant gliomas consists in surgical resection (if possible) as large as possible. The existing tools don't permit to identify the limits of tumor infiltration, which goes beyond the zone of contrast enhancement on MRI. The fluorescence-guided malignant gliomas surgery was started 15 years ago and had become a standard of care in many countries. The technique is based on fluorescent molecule revelation using the filters, positioned within the surgical microscope. The fluorophore, protoporphyrin IX (PpIX), is converted in tumoral cells from 5-aminolevulinic acid (5-ALA), given orally before surgery. Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensibility, particularly regarding the zones with poor tumoral infiltration. This book reviews the principles of the technique and the results (extent of resection and survival).

In silico modelling of apoptosis induced by photodynamic therapy.

PubMed

López-Marín, N; Mulet, R

2018-01-07

Photodynamic therapy (PDT) is an emergent technique used for the treatment of several diseases. After PDT, cells die by necrosis, apoptosis or autophagy. Necrosis is produced immediately during photodynamic therapy by high concentration of reactive oxygen species, apoptosis and autophagy are triggered by mild or low doses of light and photosensitizer. In this work we model the cell response to low doses of PDT assuming a bi-dimensional matrix of interacting cells. For each cell of the matrix we simulate in detail, with the help of the Gillespie's algorithm, the two main chemical pathways leading to apoptosis. We unveil the role of both pathways in the cell death rate of the tumor, as well as the relevance of several molecules in the process. Our model suggests values of concentrations for several species of molecules to enhance the effectiveness of PDT. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of photodynamic therapy on dermal fibroblasts from xeroderma pigmentosum and Gorlin-Goltz syndrome patients.

PubMed

Zamarrón, Alicia; García, Marta; Río, Marcela Del; Larcher, Fernando; Juarranz, Ángeles

2017-09-29

PDT is widely applied for the treatment of non-melanoma skin cancer pre-malignant and malignant lesions (actinic keratosis, basal cell carcinoma and in situ squamous cell carcinoma). In photodynamic therapy (PDT) the interaction of a photosensitizer (PS), light and oxygen leads to the formation of reactive oxygen species (ROS) and thus the selective tumor cells eradication. Xeroderma pigmentosum (XP) and Gorlin-Goltz Syndrome (GS) patients are at high risk of developing skin cancer in sun-exposed areas. Therefore, the use of PDT as a preventive treatment may constitute a very promising therapeutic modality for these syndromes. Given the demonstrated role of cancer associated fibroblasts (CAFs) in tumor progression and the putative CAFs features of some cancer-prone genodermatoses fibroblasts, in this study, we have further characterized the phenotype of XP and GS dermal fibroblasts and evaluated their response to methyl-δ-aminolevulinic acid (MAL)-PDT compared to that of dermal fibroblasts obtained from healthy donors. We show here that XP/GS fibroblasts display clear features of CAFs and present a significantly higher response to PDT, even after being stimulated with UV light, underscoring the value of this therapeutic approach for these rare skin conditions and likely to other forms of skin cancer were CAFs play a major role.

Effects of photodynamic therapy on dermal fibroblasts from xeroderma pigmentosum and Gorlin-Goltz syndrome patients

PubMed Central

Zamarrón, Alicia; García, Marta; Río, Marcela Del; Larcher, Fernando; Juarranz, Ángeles

2017-01-01

PDT is widely applied for the treatment of non-melanoma skin cancer pre-malignant and malignant lesions (actinic keratosis, basal cell carcinoma and in situ squamous cell carcinoma). In photodynamic therapy (PDT) the interaction of a photosensitizer (PS), light and oxygen leads to the formation of reactive oxygen species (ROS) and thus the selective tumor cells eradication. Xeroderma pigmentosum (XP) and Gorlin-Goltz Syndrome (GS) patients are at high risk of developing skin cancer in sun-exposed areas. Therefore, the use of PDT as a preventive treatment may constitute a very promising therapeutic modality for these syndromes. Given the demonstrated role of cancer associated fibroblasts (CAFs) in tumor progression and the putative CAFs features of some cancer-prone genodermatoses fibroblasts, in this study, we have further characterized the phenotype of XP and GS dermal fibroblasts and evaluated their response to methyl-δ-aminolevulinic acid (MAL)-PDT compared to that of dermal fibroblasts obtained from healthy donors. We show here that XP/GS fibroblasts display clear features of CAFs and present a significantly higher response to PDT, even after being stimulated with UV light, underscoring the value of this therapeutic approach for these rare skin conditions and likely to other forms of skin cancer were CAFs play a major role. PMID:29100394

Enhanced Plasmonic Resonance Energy Transfer in Mesoporous Silica-Encased Gold Nanorod for Two-Photon-Activated Photodynamic Therapy

PubMed Central

Chen, Nai-Tzu; Tang, Kuo-Chun; Chung, Ming-Fang; Cheng, Shih-Hsun; Huang, Ching-Mao; Chu, Chia-Hui; Chou, Pi-Tai; Souris, Jeffrey S.; Chen, Chin-Tu; Mou, Chung-Yuan; Lo, Leu-Wei

2014-01-01

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer. PMID:24955141

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Treatment of hidradenitis suppurativa with intralesional photodynamic therapy with 5-aminolevulinic acid and 630nm laser beam.

PubMed

Suárez Valladares, María Jesús; Eiris Salvado, Noemi; Rodríguez Prieto, Manuel Angel

2017-03-01

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease with multiple treatment options that have been used with mixed results. To evaluate the effectiveness, safety and tolerability of intralesional photodynamic therapy (I-PDT) in the management of HS. Also, to assess the effect of this technique on the different areas treated. Case series of 38 HS patients treated with I-PDT between 2011-2015 following a standardized protocol to assess response at the treated areas RESULTS: 29 patients achieved a complete response, while persistence was noted on 8 cases and only 1 suffered a recurrence. Difference between basal (median 28.5) and final (0) Hidradenitis Severity Score showed a significant reduction of 24.5 points (p<0.001, 95% OR 19.5-31). Basal (median 10) and final (1) Dermatology Life Quality Index scores reached a reduction of 10 points (p<0.001, 95%OR 8-12). Complete response was achieved in 68.2% of armpits, 88.5% of groins, 88.9% of buttocks and 100% of other locations. 18 out of 38 patients needed only a session to achieve a complete response, while maintaining a good tolerability. We believe that I-PDT might be an alternative treatment option for localized HS lesions, achieving a high rate of remission with an adequate maintenance of response i and few complications. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis

PubMed Central

Kanick, Stephen Chad; Davis, Scott C.; Zhao, Yan; Hasan, Tayyaba; Maytin, Edward V.; Pogue, Brian W.; Chapman, M. Shane

2014-01-01

Abstract. Dosimetry for aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy of actinic keratosis was examined with an optimized fluorescence dosimeter to measure PpIX during treatment. While insufficient PpIX generation may be an indicator of incomplete response, there exists no standardized method to quantitate PpIX production at depths in the skin during clinical treatments. In this study, a spectrometer-based point probe dosimeter system was used to sample PpIX fluorescence from superficial (blue wavelength excitation) and deeper (red wavelength excitation) tissue layers. Broadband white light spectroscopy (WLS) was used to monitor aspects of vascular physiology and inform a correction of fluorescence for the background optical properties. Measurements in tissue phantoms showed accurate recovery of blood volume fraction and reduced scattering coefficient from WLS, and a linear response of PpIX fluorescence versus concentration down to 1.95 and 250 nM for blue and red excitations, respectively. A pilot clinical study of 19 patients receiving 1-h ALA incubation before treatment showed high intrinsic variance in PpIX fluorescence with a standard deviation/mean ratio of >0.9. PpIX fluorescence was significantly higher in patients reporting higher pain levels on a visual analog scale. These pilot data suggest that patient-specific PpIX quantitation may predict outcome response. PMID:24996661

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.

NIR-light-induced surface-enhanced Raman scattering for detection and photothermal/photodynamic therapy of cancer cells using methylene blue-embedded gold nanorod@SiO2 nanocomposites

PubMed Central

Seo, Sun-Hwa; Kim, Bo-Mi; Joe, Ara; Han, Hyo-Won; Chen, Xiaoyuan; Cheng, Zhen; Jang, Eue-Soon

2015-01-01

Methylene blue-loaded gold nanorod@SiO2 (MB-GNR@SiO2) core@shell nanoparticles are synthesized for use in cancer imaging and photothermal/photodynamic dual therapy. For the preparation of GNR@SiO2 nanoparticles, we found that the silica coating rate of hexadecylcetyltrimethylammonium bromide (CTAB)-capped GNRs is much slower than that of PEGylated GNRs due to the densely coated CTAB bilayer. Encapsulated MB molecules have both monomer and dimer forms that result in an increase in the photosensitizing effect through different photochemical pathways. As a consequence of the excellent plasmonic properties of GNRs at near-infrared (NIR) light, the embedded MB molecules showed NIR light-induced SERS performance with a Raman enhancement factor of 3.0 × 1010, which is enough for the detection of a single cancer cell. Moreover, the MB-GNR@SiO2 nanoparticles exhibit a synergistic effect of photodynamic and photothermal therapies of cancer under single-wavelength NIR laser irradiation. PMID:24424205

Effectiveness of Photodynamic Therapy in Elimination of HPV-16 and HPV-18 Associated with CIN I in Mexican Women.

PubMed

Maldonado Alvarado, Elizabeth; Osorio Peralta, Martha Olivia; Moreno Vázquez, Alejandra; Martínez Guzmán, Lydia Alejandra; Melo Petrone, Maria Eugenia; Enriquez Mar, Zulma Iveth; Jovel Galdamez, Dora Estela; Carrión Solana, Bárbara; Balderas Martínez, Guadalupe; Parra, Eduarda; Castellanos Oliveros, Rossana Inés; Bello Leiva, Rosa Linda; Espinosa Montesinos, Araceli; Barrera Mendoza, Citlalli; Medina García, Selma Eugenia; Ramón Gallegos, Eva

2017-10-01

This study aimed to determine the effectiveness of photodynamic therapy (PDT), using δ-aminolevulinic acid (5-ALA), in the elimination of premalignant cervical lesions in Mexican patients with human papillomavirus (HPV) infection and/or cervical intraepithelial neoplasia (CIN). Thirty women diagnosed with CIN I and/or positive for HPV participated in the study. Topical 6% 5-ALA in gel form was applied to the uterine cervix; after 4 h, the lesion area was irradiated with a light dose of 200 J cm -2 at 635 nm. This procedure was performed three times at 48-h intervals. Clinical follow-up was performed at 3, 6, and 12 months after the initial PDT administration, by colposcopy, cervical cytology, histopathological analysis, polymerase chain reaction, and hybrid capture. Of HPV-infected patients without evidence of CIN I, 80% cleared the infection, while HPV associated with CIN I was eliminated in 83% of patients (P < 0.05). At 12 months, CIN I had regressed in 57% of patients, although this response was not statistically significant. PDT using 6% 5-ALA is concluded to be effective in eliminating HPV infection associated or not with CIN I. © 2017 The American Society of Photobiology.

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.

In vitro bactericidal activity of 465-470 nm blue light phototherapy and aminolevulinic acid on Staphylococcus pseudintermedius.

PubMed

Bae, Seulgi; Oh, Taeho

2018-05-30

Staphylococcus pseudintermedius is the principal pathogen causing bacterial skin infections in dogs. Photodynamic therapy (PDT) involving the combination of light and a topical photosensitizer is used to treat human skin infections. Although the antimicrobial effects of PDT have been demonstrated using in vivo and in vitro studies in humans, its effects on dogs and their pathogens are unclear. The aim of this study was to demonstrate the in vitro efficacy of PDT over a 465-470 nm spectrum to kill S. pseudintermedius using δ-aminolevulinic acid (ALA) as the photosensitizer. Six S. pseudintermedius isolates from canine skin were exposed to blue light-emitting diodes (LEDs) at 465-470 nm, with or without ALA. The light doses were 18.4, 36.8 and 55.2 J/cm 2 . The number of colony-forming units and optical densities of broth cultures were measured and then compared with Dunnett's test. Bacterial viability was monitored using fluorescence microscopy and the fluorescence intensity values were compared with a paired Student's t-test. Blue light inhibited the growth of S. pseudintermedius; the effect significantly increased with the addition of ALA as a photosensitizer and with increasing light doses. Live/dead staining confirmed that PDT reduced bacterial viability and exerted an antibacterial effect. Blue light has a strong antibacterial effect on S. pseudintermedius in a light dose-dependent manner. ALA alone did not exhibit bactericidal action, but its combination with blue light increased the effect of PDT compared to blue light alone. © 2018 ESVD and ACVD.

Daylight methyl-aminolevulinate photodynamic therapy versus ingenol mebutate for the treatment of actinic keratoses: an intraindividual comparative analysis.

PubMed

Genovese, Giovanni; Fai, Dario; Fai, Carlotta; Mavilia, Luciano; Mercuri, Santo R

2016-05-01

Daylight-photodynamic therapy (D-PDT) and ingenol mebutate (IM) are novel therapies directed to actinic keratoses (AK). The purpose of our study was to compare effectiveness, tolerability, cosmetic outcome and patient preference of D-PDT versus IM in the treatment of grade I and II AK. Twenty-seven patients with AK on the face or scalp were enrolled. Each patient received, in a 25 cm(2) target area, D-PDT on right side and IM on left side. Overall 323 AK were treated. Both target areas achieved complete response in 40.47% of the cases and average AK clearance rate was similar for D-PDT and IM (p=0.74). In D-PDT areas mean grade II AK clearance rate was lower compared with that of grade I AK (p=0.015). In IM areas grade I and II AK average clearance rates were similar (p=0.28). At week 1 and month 1, mean local skin responses (LSR) score were higher in areas treated with IM. IM areas showed more severe pain and cosmetic sequelae. D-PDT had similar effectiveness to IM, even if IM demonstrated higher grade II AK clearance rate. Tolerability profile was superior for D-PDT in terms of LSR and pain. D-PDT was more cosmetically acceptable. Patients preferred D-PDT to IM in most cases. © 2016 Wiley Periodicals, Inc.

Targeting Antitumor Immune Response for Enhancing the Efficacy of Photodynamic Therapy of Cancer: Recent Advances and Future Perspectives

PubMed Central

2016-01-01

Photodynamic therapy (PDT) is a minimally invasive therapeutic strategy for cancer treatment, which can destroy local tumor cells and induce systemic antitumor immune response, whereas, focusing on improving direct cytotoxicity to tumor cells treated by PDT, there is growing interest in developing approaches to further explore the immune stimulatory properties of PDT. In this review we summarize the current knowledge of the innate and adaptive immune responses induced by PDT against tumors, providing evidence showing PDT facilitated-antitumor immunity. Various immunotherapeutic approaches on different cells are reviewed for their effectiveness in improving the treatment efficiency in concert with PDT. Future perspectives are discussed for further enhancing PDT efficiency via intracellular targetable drug delivery as well as optimized experimental model development associated with the study of antitumor immune response. PMID:27672421

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

A New Modality for Cancer Treatment--Nanoparticle Mediated Microwave Induced Photodynamic Therapy.

PubMed

Yao, Mengyu; Ma, Lun; Li, Lihua; Zhang, Junying; Lim, Rebecca; Chen, Wei; Zhang, Yu

2016-10-01

Photodynamic therapy (PDT) has attracted ever-growing attention as a promising modality for cancer treatment. However, due to poor tissue penetration by light, photodynamic therapy has rarely been used for deeply situated tumors. This problem can be solved if photosensitizers are activated by microwaves (MW) that are able to penetrate deeply into tissues. Here, for the first time, we report microwave-induced photodynamic therapy and exploit copper cysteamine nanoparticles as a new type of photosensitizer that can be activated by microwaves to produce singlet oxygen for cancer treatment. Both in vitro and in vivo studies on a rat osteosarcoma cell line (UMR 106-01) have shown significant cell destruction using copper cysteamine (Cu-Cy) under microwave activation. The heating effects and the release of copper ions from Cu-Cy upon MW stimulation are the main mechanisms for the generation of reactive oxygen species that are lethal bullets for cancer destruction. The copper cysteamine nanoparticle-based microwave-induced photodynamic therapy opens a new door for treating cancer and other diseases.

Photodynamic therapy influence on anti-cancer immunity

NASA Astrophysics Data System (ADS)

Isaeva, O. G.; Osipov, V. A.

2010-02-01

The system of partial differential equations describing tumor-immune dynamics with angiogenesis taken into account is presented. For spatially homogeneous case, the steady state analysis of the model is carried out. The effects of single photodynamic impact are numerically simulated. In the case of strong immune response we found that the photodynamic therapy (PDT) gives rise to the substantial shrinkage of tumor size which is accompanied by the increase of IL-2 concentration. On the contrary, the photodynamic stimulation of weak immune response is shown to be insufficient to reduce the tumor. These findings indicate the important role of anti-cancer immune response in the long-term tumor control after PDT.

Photodynamic therapy influence on anti-cancer immunity

NASA Astrophysics Data System (ADS)

Isaeva, O. G.; Osipov, V. A.

2009-10-01

The system of partial differential equations describing tumor-immune dynamics with angiogenesis taken into account is presented. For spatially homogeneous case, the steady state analysis of the model is carried out. The effects of single photodynamic impact are numerically simulated. In the case of strong immune response we found that the photodynamic therapy (PDT) gives rise to the substantial shrinkage of tumor size which is accompanied by the increase of IL-2 concentration. On the contrary, the photodynamic stimulation of weak immune response is shown to be insufficient to reduce the tumor. These findings indicate the important role of anti-cancer immune response in the long-term tumor control after PDT.

In vivo 808 nm image-guided photodynamic therapy based on an upconversion theranostic nanoplatform

NASA Astrophysics Data System (ADS)

Liu, Xiaomin; Que, Ivo; Kong, Xianggui; Zhang, Youlin; Tu, Langping; Chang, Yulei; Wang, Tong Tong; Chan, Alan; Löwik, Clemens W. G. M.; Zhang, Hong

2015-09-01

A new strategy for efficient in vivo image-guided photodynamic therapy (PDT) has been demonstrated utilizing a ligand-exchange constructed upconversion-C60 nanophotosensitizer. This theranostic platform is superior to the currently reported nanophotosensitizers in (i) directly bonding photosensitizer C60 to the surface of upconversion nanoparticles (UCNPs) by a smart ligand-exchange strategy, which greatly shortened the energy transfer distance and enhanced the 1O2 production, resulting in the improvement of the therapeutic effect; (ii) realizing in vivo NIR 808 nm image-guided PDT with both excitation (980 nm) and emission (808 nm) light falling in the biological window of tissues, which minimized auto-fluorescence, reduced light scatting and improved the imaging contrast and depth, and thus guaranteed noninvasive diagnostic accuracy. In vivo and ex vivo tests demonstrated its favorable bio-distribution, tumor-selectivity and high therapeutic efficacy. Owing to the effective ligand exchange strategy and the excellent intrinsic photophysical properties of C60, 1O2 production yield was improved, suggesting that a low 980 nm irradiation dosage (351 J cm-2) and a short treatment time (15 min) were sufficient to perform NIR (980 nm) to NIR (808 nm) image-guided PDT. Our work enriches the understanding of UCNP-based PDT nanophotosensitizers and highlights their potential use in future NIR image-guided noninvasive deep cancer therapy.A new strategy for efficient in vivo image-guided photodynamic therapy (PDT) has been demonstrated utilizing a ligand-exchange constructed upconversion-C60 nanophotosensitizer. This theranostic platform is superior to the currently reported nanophotosensitizers in (i) directly bonding photosensitizer C60 to the surface of upconversion nanoparticles (UCNPs) by a smart ligand-exchange strategy, which greatly shortened the energy transfer distance and enhanced the 1O2 production, resulting in the improvement of the therapeutic effect; (ii

A multicenter, randomized, vehicle-controlled phase 2 study of blue light photodynamic therapy with aminolevulinic acid HCl 20% topical solution for the treatment of actinic keratoses on the upper extremities: the effect of occlusion during the drug incubation period.

PubMed

Schmieder, George J; Huang, Eugene Y; Jarratt, Michael

2012-12-01

Photodynamic therapy (PDT) with aminolevulinic acid (ALA) has been shown to be safe and effective in the treatment of actinic keratoses (AKs) of the face and scalp. A recent small study has suggested that ALA-PDT can be effective for AKs of the dorsal hands/forearms. However, studies designed to provide sufficient statistical power to test this hypothesis are lacking in the literature. To determine and compare the safety and efficacy of blue light ALA-PDT vs blue light placebo vehicle (VEH) in the treatment of AKs of the upper extremities and to evaluate the effect of occlusion after application of ALA vs VEH. ALA or VEH was applied to both dorsal hands/forearms for the 3-hour incubation period before blue light treatment (10 J/ cm2). One extremity of each subject was covered with occlusive dressing during the incubation period. Treatment was repeated at week 8 if any AK lesions remained. The median AK lesion clearance rate at week 12 was 88.7% for extremities treated with occluded ALA (ALA+OCC), 70.0% for extremities treated with nonoccluded ALA, 16.7% for extremities treated with occluded VEH (VEH+OCC), and 5.6% for extremities treated with nonoccluded VEH (P<.0001). ALA+OCC resulted in a significantly higher clearance rate compared with the nonoccluded extremity at weeks 8 (P=.0006) and 12 (P=.0029). Thirty-four percent (12/35) of extremities treated with ALA+OCC had complete clearance of lesions at week 12 compared with 0% (0/35) of extremities treated with VEH+OCC (P=.0002). The safety pro!le in this study is consistent with previously reported side effects of the therapy. Blue light ALA-PDT following a 3-hour incubation appears efficacious for AK clearance of the upper extremities. Incubation using an occlusive dressing significantly increases the efficacy of the procedure and also increases the incidence and severity of some acute inflammatory side effects of PDT.

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.

A Cell-targeted Photodynamic Nanomedicine Strategy for Head & Neck Cancers

PubMed Central

Master, Alyssa; Malamas, Anthony; Solanki, Rachna; Clausen, Dana M.; Eiseman, Julie L.; Gupta, Anirban Sen

2013-01-01

Photodynamic Therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intra-tumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise towards a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas. PMID:23531079

Attaching NorA efflux pump inhibitors to methylene blue enhances antimicrobial photodynamic inactivation of Escherichia coli and Acinetobacter baumannii in vitro and in vivo.

PubMed

Rineh, Ardeshir; Bremner, John B; Hamblin, Michael R; Ball, Anthony R; Tegos, George P; Kelso, Michael J

2018-02-24

Resistance of bacteria to antibiotics is a public health concern worldwide due to the increasing failure of standard antibiotic therapies. Antimicrobial photodynamic inactivation (aPDI) is a promising non-antibiotic alternative for treating localized bacterial infections that uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species and kill microbes. Phenothiazinium photosensitizers like methylene blue (MB) and toluidine blue O are hydrophobic cations that are naturally expelled from bacterial cells by multidrug efflux pumps, which reduces their effectiveness. We recently reported the discovery of a NorA efflux pump inhibitor-methylene blue (EPI-MB) hybrid compound INF55-(Ac)en-MB that shows enhanced photodynamic inactivation of the Gram-positive bacterium methicillin-resistant Staphylococcus aureus (MRSA) relative to MB, both in vitro and in vivo. Here, we report the surprising observation that INF55-(Ac)en-MB and two related hybrids bearing the NorA efflux pump inhibitors INF55 and INF271 also show enhanced aPDI activity in vitro (relative to MB) against the Gram-negative bacteria Escherichia coli and Acinetobacter baumannii, despite neither species expressing the NorA pump. Two of the hybrids showed superior effects to MB in murine aPDI infection models. The findings motivate wider exploration of aPDI with EPI-MB hybrids against Gram-negative pathogens and more detailed studies into the molecular mechanisms underpinning their activity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hydrophilic Chlorin e6-Poly(amidoamine) Dendrimer Nanoconjugates for Enhanced Photodynamic Therapy.

PubMed

Lee, So-Ri; Kim, Young-Jin

2018-06-18

In photodynamic therapy (PDT), chlorin e6 (Ce6), with its high phototoxic potential and strong absorption of visible light, penetrates deeply into photodamaged tissue. However, despite this fact, the direct application of Ce6 to PDT has been limited by its low water solubility and poor cancer cell localization. To ameliorate this situation, we report herein on the use of a hydrophilic nanoconjugate (DC) comprised of Ce6 and poly(amidoamine) dendrimer, which improves the water solubility and intracellular uptake of Ce6, thereby enhancing PDT efficacy. The synthesis of DC was verified by ¹H nuclear magnetic resonance (NMR) analysis, and the coupling ratio of Ce6 introduced onto DC was 2.64. The prepared DC was spherical, with an average diameter of 61.7 ± 3.5 nm. In addition, the characteristic ultraviolet-visible absorption bands of DC in distilled water were similar to those of free Ce6 in dimethyl sulfoxide (DMSO), indicating that the Ce6 chromophore did not change upon conjugation. Investigation using fluorescence spectroscopy and confocal microscopy revealed a greater intracellular uptake of DC than of Ce6 alone. Moreover, DC exhibited significantly increased phototoxicity to human cervical cancer cells, mostly because of apoptotic cell death. These results imply that DC is a candidate for the clinical treatment of PDT.

Attempted photodynamic therapy against patagial squamous cell carcinoma in an African rose-ringed parakeet (Psittacula krameri).

PubMed

Suedmeyer, Wm Kirk; Henry, Carolyn; McCaw, Dudley; Boucher, Magalie

2007-12-01

A 5-yr-old female African rose-ringed parakeet (Psittacula krameri) presented with an ulcerated mass in the medial postpatagial area of the right wing. Biopsy specimens of the mass demonstrated a well-differentiated squamous cell carcinoma. Photodynamic therapy resulted in tumor cell necrosis and initial reduction in tumor burden, but complete remission was not achieved. Based on this and other avian cases, it appears that photodynamic therapy designed to eradicate squamous cell carcinoma in avian species using protocols modeled after canine, feline, and human photodynamic therapy protocols may not be useful. It is hypothesized that differences in light penetration, photosensitizing agent pharmacokinetics, and wound healing properties in avian species necessitate alteration of photodynamic therapy protocols if this treatment modality is to be effective in avian oncology.

Virus-Based Cancer Therapeutics for Targeted Photodynamic Therapy.

PubMed

Cao, Binrui; Xu, Hong; Yang, Mingying; Mao, Chuanbin

2018-01-01

Cancer photodynamic therapy (PDT) involves the absorption of light by photosensitizers (PSs) to generate cytotoxic singlet oxygen for killing cancer cells. The success of this method is usually limited by the lack of selective accumulation of the PS at cancer cells. Bioengineered viruses with cancer cell-targeting peptides fused on their surfaces are great drug carriers that can guide the PS to cancer cells for targeted cancer treatment. Here, we use cell-targeting fd bacteriophages (phages) as an example to describe how to chemically conjugate PSs (e.g., pyropheophorbide-a (PPa)) onto a phage particle to achieve targeted PDT.

Diagnosis of upper urinary tract tumours: is photodynamic diagnosis assisted ureterorenoscopy required as an addition to modern imaging and ureterorenoscopy?

PubMed

Aboumarzouk, Omar M; Mains, Edward; Moseley, Harry; Kata, Sławomir G

2013-05-01

We aimed to assess the diagnostic accuracy of photodynamic diagnostic ureterorenoscopy (PDD-FURS) in detection of UUT-TCC in comparison with CT Urogram (CTU) and WL-FURS. Between June 2009 and August 2011, 30 patients underwent PDD-FURS after CTU for suspicion of UUT-TCC. Ureterorenoscopy was performed for abnormal upper urinary tract on imaging. Oral 5-Aminolevulinic Acid (5-ALA) was used as a photosensitizer. All procedures were performed by single endourologist experienced in photodynamic diagnosis. The sensitivity, specificity, and detection rate of WL-FURS, PDD-FURS and CTU were calculated using the Meta-DiSc v1.4 programme. P values <0.05 were considered significant. PDD-FURS detected more UUT-TCCs than CTU or WL-FURS (94% (16/17) vs. 76.5% (13/17) vs. 82% (14/17) respectively). PDD-FURS was not significantly more sensitive than CTU and WL-FURS to detect UUT-TCC (0.94 (95% CI: 0.71-0.99) vs. 0.82 (95% CI: 0.57-0.96) vs. 0.81 (95% CI: 0.54-0.96) respectively; PDD-FURS vs. CTU: P=0.249; PDD-FURS vs. WL-FURS: P=0.277). There was no difference in the specificity between PDD-FURS and WL-FURS (1.0 (95% CI: 0.75-1.0) and 1.0 (95% CI: 0.75-1.0) respectively) (P=1), while PDD-FURS was significantly more specific than CTU (CTU: 0.21 (95% CI: 0.05-0.51) (P<0.001). PDD-FURS picked up 3 cases of CIS, which was not seen on WL-FURL and CTU. Oral 5-ALA induced PDD-FURS has a high sensitivity and specificity to detect lesions and a higher detection rate to diagnose UUT-TCC than WL-FURS and CTU. It appears to be the only tool to visualise UUT CIS lesions. Copyright © 2012 Elsevier B.V. All rights reserved.

Photodynamic Effect of Ni Nanotubes on an HeLa Cell Line

PubMed Central

Hammad Aziz, Muhammad; Fakhar-e-Alam, M.; Fatima, Mahvish; Shaheen, Fozia; Iqbal, Seemab; Atif, M.; Talha, Muhammad; Mansoor Ali, Syed; Afzal, Muhammad; Majid, Abdul; Shelih Al.Harbi, Thamir; Ismail, Muhammad; Wang, Zhiming M.; AlSalhi, M. S.; Alahmed, Z. A.

2016-01-01

Nickel nanomaterials are promising in the biomedical field, especially in cancer diagnostics and targeted therapy, due to their distinctive chemical and physical properties. In this experiment, the toxicity of nickel nanotubes (Ni NTs) were tested in an in vitro cervical cancer model (HeLa cell line) to optimize the parameters of photodynamic therapy (PDT) for their greatest effectiveness. Ni NTs were synthesized by electrodeposition. Morphological analysis and magnetic behavior were examined using a Scanning electron microscope (SEM), an energy dispersive X-ray analysis (EDAX) and a vibrating sample magnetometer (VSM) analysis. Phototoxic and cytotoxic effects of nanomaterials were studied using the Ni NTs alone as well as in conjugation with aminolevulinic acid (5-ALA); this was performed both in the dark and under laser exposure. Toxic effects on the HeLa cell model were evaluated by a neutral red assay (NRA) and by detection of intracellular reactive oxygen species (ROS) production. Furthermore, 10–200 nM of Ni NTs was prepared in solution form and applied to HeLa cells in 96-well plates. Maximum toxicity of Ni NTs complexed with 5-ALA was observed at 100 J/cm2 and 200 nM. Up to 65–68% loss in cell viability was observed. Statistical analysis was performed on the experimental results to confirm the worth and clarity of results, with p-values = 0.003 and 0.000, respectively. Current results pave the way for a more rational strategy to overcome the problem of drug bioavailability in nanoparticulate targeted cancer therapy, which plays a dynamic role in clinical practice. PMID:26990435

Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer.

PubMed

McEwan, Conor; Nesbitt, Heather; Nicholas, Dean; Kavanagh, Oisin N; McKenna, Kevin; Loan, Philip; Jack, Iain G; McHale, Anthony P; Callan, John F

2016-07-01

Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions. Copyright © 2016. Published by Elsevier Ltd.

Aspect ratio dependence of the enhancement of fluorescence intensity by gold nanobipyramids for cancer cell imaging and photodynamic therapy

NASA Astrophysics Data System (ADS)

Wang, Jing; Wang, Shimiao; Mi, Lan; Liu, Jun

2018-07-01

Enhancement of dye fluorescence intensity was studied by modifying the aspect ratio of gold nanobipyramids (AuBPs) from 3.2 to 6.6. The emission fluorescence intensity of sulfonated aluminum phthalocyanine (AlPcS) was strongly dependent on the aspect ratio of AuBPs. Furthermore, we found that the energy transfer from excited AlPcS to AuBPs was a key determinant of the efficacy of metal-enhanced fluorescence. By means of AuBPs with a higher aspect ratio, such that the surface plasmon resonance band does not overlap with the energy level of excited AlPcS, metal-enhanced fluorescence of various AlPcS–AuBP conjugates was determined, and the maximal enhancement factor was found to be 14. The enhanced fluorescence intensity of AlPcS conjugated with AuBPs indicates promising plasmonic properties. An apoptosis assay of HeLa cells revealed that AlPcS–AuBPs, when used as a drug, can enhance the effectiveness of photodynamic therapy (PDT). Furthermore, AuBPs with the longitudinal absorption peak wavelength of 1050 nm had optimal proapoptotic effects. HeLa cells treated with AlPcS–AuBPs (ratio 0.42 µM to 0.01 nM) had viability as low as 29.31% after 32 J cm‑2 ultraviolet light exposure, indicating the strong potential of AlPcS–AuBPs to improve the efficacy of PDT.

NIR-light-induced surface-enhanced Raman scattering for detection and photothermal/photodynamic therapy of cancer cells using methylene blue-embedded gold nanorod@SiO2 nanocomposites.

PubMed

Seo, Sun-Hwa; Kim, Bo-Mi; Joe, Ara; Han, Hyo-Won; Chen, Xiaoyuan; Cheng, Zhen; Jang, Eue-Soon

2014-03-01

Methylene blue-loaded gold nanorod@SiO2 (MB-GNR@SiO2) core@shell nanoparticles are synthesized for use in cancer imaging and photothermal/photodynamic dual therapy. For the preparation of GNR@SiO2 nanoparticles, we found that the silica coating rate of hexadecylcetyltrimethylammonium bromide (CTAB)-capped GNRs is much slower than that of PEGylated GNRs due to the densely coated CTAB bilayer. Encapsulated MB molecules have both monomer and dimer forms that result in an increase in the photosensitizing effect through different photochemical pathways. As a consequence of the excellent plasmonic properties of GNRs at near-infrared (NIR) light, the embedded MB molecules showed NIR light-induced SERS performance with a Raman enhancement factor of 3.0 × 10(10), which is enough for the detection of a single cancer cell. Moreover, the MB-GNR@SiO2 nanoparticles exhibit a synergistic effect of photodynamic and photothermal therapies of cancer under single-wavelength NIR laser irradiation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nanoscale metal-organic frameworks for photodynamic therapy and cancer immunotherapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Lin, Wenbin

2017-02-01

Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species. We recently reported the rational design of a Hf-porphyrin nanoscale metal-organic framework, DBP-UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP-UiO efficiently generates singlet oxygen owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile singlet oxygen diffusion through porous DBP-UiO nanoplates. Consequently, DBP-UiO displayed greatly enhanced PDT efficacy both in vitro and in vivo, leading to complete tumor eradication in half of the mice receiving a single DBP-UiO dose and a single light exposure. The photophysical properties of DBP-UiO are however not optimum with the lowest energy absorption at 634 nm and a relatively small extinction coefficient of 2200 M-1·cm-1. We recently designed a chlorin-based NMOF, DBC-UiO, with much improved photophysical properties and PDT efficacy in two colon cancer mouse models. Reduction of the DBP ligands in DBP-UiO to the DBC ligands in DBC-UiO led to a 13 nm red-shift and an 11-fold extinction coefficient increase of the lowest energy Q-band. While inheriting the crystallinity, stability, porosity, and nanoplate morphology of DBP-UiO, DBC-UiO sensitizes more efficient singlet oxygen generation and exhibits much enhanced photodynamic therapy (PDT) efficacy on two colon cancer mouse models as a result of its improved photophysical properties. Both apoptosis and immunogenic cell death contributed to cancer cell-killing in DBC-UiO induced PDT. Our work has thus demonstrated that NMOFs represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic.

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.

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.

Photodynamic therapy for actinic cheilitis: a systematic review.

PubMed

Yazdani Abyaneh, Mohammad-Ali; Falto-Aizpurua, Leyre; Griffith, Robert D; Nouri, Keyvan

2015-02-01

Actinic cheilitis (AC) is a premalignant lesion of the lips that can progress to squamous cell carcinoma and metastasize. Actinic cheilitis is difficult to treat because surgical treatments have significant adverse effects whereas less invasive procedures have uncertain efficacy. Photodynamic therapy (PDT) may offer a noninvasive yet effective treatment option for AC. To systematically review the safety and efficacy of PDT for AC. The terms "photodynamic," "actinic," "solar," "cheilitis," and "cheilosis" were used in combinations to search the PubMed database. Studies were considered for inclusion based on eligibility criteria, and specific data were extracted from all studies. The authors identified 15 eligible case series encompassing a total of 242 treated subjects. Among studies that evaluated subjects for complete clinical response, 139 of 223 subjects (62%) showed complete response at final follow-ups ranging from 3 to 30 months. Among studies that evaluated subjects for histological outcome, 57 of 121 subjects (47%) demonstrated histological cure at final follow-ups ranging from 1.5 to 18 months. Cosmetic outcomes were good to excellent in the majority of subjects, and adverse events were well tolerated. Photodynamic therapy is safe and has the potential to clinically and histologically treat AC, with a need for future randomized controlled trials.

Involvement of Bim in Photofrin-mediated photodynamically induced apoptosis.

PubMed

Wang, Xianwang; He, Xiaobing; Hu, Shujuan; Sun, Anbang; Lu, Chengbiao

2015-01-01

Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells. The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT-induced apoptosis was determined by RNAi. BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA-Bim. We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers. © 2015 S. Karger AG, Basel.

Photodynamic therapy for treatment subretinal neovascularization

NASA Astrophysics Data System (ADS)

Avetisov, Sergey E.; Budzinskaja, Maria V.; Kiseleva, Tatyana N.; Balatskaya, Natalia V.; Gurova, Irina V.; Loschenov, Viktor B.; Shevchik, Sergey A.; Kuzmin, Sergey G.; Vorozhtsov, Georgy N.

2007-07-01

This work are devoted our experience with photodynamic therapy (PDT) with <> for patients with choroidal neovascularization (CNV). 18 patients with subfoveal CNV in age-related macular degeneration (AMD), 24 patients with subfoveal CNV in pathological myopia (PM) and 4 patients with subfoveal CNV associated with toxoplasmic retinochoroiditis were observed. CNV was 100% classic in all study patients. Standardized protocol refraction, visual acuity testing, ophthalmologic examinations, biomicroscopy, fluorescein angiography, and ultrasonography were performed before treatment and 1 month, 3 months, 6 months, and 1 year after treatment; were used to evaluate the results of photodynamic therapy with <> (0.02% solution of mixture sulfonated aluminium phtalocyanine 0.05 mg/kg, intravenously). A diode laser (<>, Inc, Moscow) was used operating in the range of 675 nm. Need for retreatment was based on fluorescein angiographic evidence of leakage at 3-month follow-up intervals. At 3, 6, 9 month 26 (56.5%) patients had significant improvement in the mean visual acuity. At the end of the 12-month minimal fluorescein leakage from choroidal neovascularization was seen in 12 (26.1%) patients and the mean visual acuity was slightly worse than 0.2 which was not statistically significant as compared with the baseline visual acuity. Patients with fluorescein leakage from CNV underwent repeated PDT with <>. 3D-mode ultrasound shown the decreasing thickness of chorioretinal complex in CNV area. Photodynamic therapy with <> can safely reduce the risk of severe vision loss in patients with predominantly classic subfoveal choroidal neovascularization secondary to AMD, PM and toxoplasmic retinochoroiditis.

Phthalocyanine-sulfonamide conjugates: Synthesis and photodynamic inactivation of Gram-negative and Gram-positive bacteria.

PubMed

da Silva, Raquel Nunes; Cunha, Ângela; Tomé, Augusto C

2018-06-25

Phthalocyanines bearing four or eight sulfonamide units were synthesized and their efficiency in the photodynamic inactivation of Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria was evaluated. Conjugates with simpler sulfonamide units (N,N-diethylbenzenesulfonamide, N-isopropylbenzenesulfonamide and N-(4-methoxyphenyl)benzenesulfonamide) caused stronger inactivation than those with heterocyclic groups (N-(thiazol-2-yl)benzenesulfonamide) or long alkyl chains (N-dodecylbenzenesulfonamide) in both bacteria. Furthermore, the encapsulation of the phthalocyanine-sulfonamide conjugates within polyvinylpyrrolidone micelles, used as drug delivery vehicles, in general showed to enhance the inactivation efficiency. The results show that encapsulated phthalocyanine-sulfonamide conjugates are a promising class of photosensitizers to be used in photodynamic antimicrobial therapy. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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

Enhancing early bladder cancer detection with fluorescence-guided endoscopic optical coherence tomography

NASA Astrophysics Data System (ADS)

Pan, Y. T.; Xie, T. Q.; Du, C. W.; Bastacky, S.; Meyers, S.; Zeidel, M. L.

2003-12-01

We report an experimental study of the possibility of enhancing early bladder cancer diagnosis with fluorescence-image-guided endoscopic optical coherence tomography (OCT). After the intravesical instillation of a 10% solution of 5-aminolevulinic acid, simultaneous fluorescence imaging (excitation of 380-420 nm, emission of 620-700 nm) and OCT are performed on rat bladders to identify the photochemical and morphological changes associated with uroepithelial tumorigenesis. The preliminary results of our ex vivo study reveal that both fluorescence and OCT can identify early uroepithelial cancers, and OCT can detect precancerous lesions (e.g., hyperplasia) that fluorescence may miss. This suggests that a cystoscope combining 5-aminolevulinic acid fluorescence and OCT imaging has the potential to enhance the efficiency and sensitivity of early bladder cancer diagnosis.

The time-dependent accumulation of protoporphyrin IX fluorescence in nodular basal cell carcinoma following application of methyl aminolevulinate with an oxygen pressure injection device.

PubMed

Blake, E; Campbell, S; Allen, J; Mathew, J; Helliwell, P; Curnow, A

2012-12-05

Topical protoporphyrin (PpIX)-induced photodynamic therapy (PDT) relies on the penetration of the prodrug into the skin lesion and subsequent accumulation of the photosensitizer. Methyl aminolevulinate (MAL)-PDT is an established treatment for thinner and superficial non-melanoma skin cancers (NMSCs) but for the treatment of the thicker nodular basal cell carcinoma (nBCC) enhanced penetration of the prodrug is required. This study employed a new higher pressure, oxygen pressure injection (OPI) device, at the time of Metvix® application with a view to enhancing the penetration of MAL into the tumors. Each patient had Metvix® applied to a single nBCC followed by application of a higher pressure OPI device. Following different time intervals (0, 30, 60, 120 or 180 min) the tumors were excised. The maximum depth and area of MAL penetration achieved in each lesion was measured using PpIX fluorescence microscopy. As expected, an increase in the depth of MAL-induced PpIX accumulation and area of tumor sensitized was observed over time; when the Metvix® cream was applied for 0, 30, 60, 120 and 180 min the median depth of PpIX fluorescence was 0%, 21%, 26.5%, 75.5% and 90%, respectively and the median area of tumor sensitized was 0%, 4%, 6%, 19% and 60%, respectively. As the investigation presented here did not include a control arm, the relative depths of fluorescence observed in this study were statistically compared (using the non-parametric Mann Whitney U test) with the results of our previous study where patients had Metvix® cream applied either with or without the standard pressure OPI device. When the higher pressure OPI device was employed compared to without OPI this increase was observed to be greater following 30, 120, and 180 min although overall not significantly (p=0.835). In addition, no significant difference between the higher pressure OPI device employed here and the previously investigated standard pressure OPI device was observed (p=0.403). However

Optical and photoacoustic dual-modality imaging guided synergistic photodynamic/photothermal therapies

NASA Astrophysics Data System (ADS)

Yan, Xuefeng; Hu, Hao; Lin, Jing; Jin, Albert J.; Niu, Gang; Zhang, Shaoliang; Huang, Peng; Shen, Baozhong; Chen, Xiaoyuan

2015-01-01

Phototherapies such as photodynamic therapy (PDT) and photothermal therapy (PTT), due to their specific spatiotemporal selectivity and minimal invasiveness, have been widely investigated as alternative treatments of malignant diseases. Graphene and its derivatives not only have been used as carriers to deliver photosensitizers for PDT, but also as photothermal conversion agents (PTCAs) for PTT. Herein, we strategically designed and produced a novel photo-theranostic platform based on sinoporphyrin sodium (DVDMS) photosensitizer-loaded PEGylated graphene oxide (GO-PEG-DVDMS) for enhanced fluorescence/photoacoustic (PA) dual-modal imaging and combined PDT and PTT. The GO-PEG carrier drastically improves the fluorescence of loaded DVDMS via intramolecular charge transfer. Concurrently, DVDMS significantly enhances the near-infrared (NIR) absorption of GO for improved PA imaging and PTT. The cancer theranostic capability of the as-prepared GO-PEG-DVDMS was carefully investigated both in vitro and in vivo. This novel theranostics is well suited for fluorescence/PA dual-modal imaging and synergistic PDT/PTT.

ALA-PDT mediated DC vaccine for skin squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Ji, Jie; Fan, Zhixia; Zhou, Feifan; Wang, Xiaojie; Shi, Lei; Zhang, Haiyan; Wang, Peiru; Yang, Degang; Zhang, Linglin; Wang, Xiuli; Chen, Wei R.

2015-03-01

Dendritic cell (DC) based vaccine has emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have only achieved limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secret INF-Υ and IL-12). ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumor in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing DC-based cancer vaccine, which could improve the clinical application of PDT- DC vaccines.

Singlet oxygen and ROS in a new light: low-dose subcellular photodynamic treatment enhances proliferation at the single cell level.

PubMed

Blázquez-Castro, Alfonso; Breitenbach, Thomas; Ogilby, Peter R

2014-09-01

Two-photon excitation of a sensitizer with a focused laser beam was used to create a spatially-localized subcellular population of reactive oxygen species, ROS, in single HeLa cells. The sensitizer used was protoporphyrin IX, PpIX, endogenously derived from 5-aminolevulinic acid delivered to the cells. Although we infer that singlet oxygen, O2(a(1)Δg), is one ROS produced upon irradiation of PpIX under these conditions, it is possible that the superoxide ion, O2(-˙), may also play a role in this system. With a "high" dose of PpIX-sensitized ROS, the expected death of the cell was observed. However, under "low dose" conditions, clear signs of cell proliferation were observed. The present results facilitate studies of ROS-mediated signalling in imaging-based single cell experiments.

Fluorescence detection of malignant liver tumors using 5-aminolevulinic acid-mediated photodynamic diagnosis: principles, technique, and clinical experience.

PubMed

Inoue, Yoshihiro; Tanaka, Ryo; Komeda, Koji; Hirokawa, Fumitoshi; Hayashi, Michihiro; Uchiyama, Kazuhisa

2014-07-01

Photoactive drugs selectively accumulate in malignant tissue specimens and cause drug-induced fluorescence. Photodynamic diagnosis (PDD) and fluorescence can distinguish normal from malignant tissue. From May 2012 to September 2013, a total of 70 patients underwent hepatic resections using 5-ALA-mediated PDD for liver tumors at our hospital. 5-ALA fluorescence was detected in all hepatocellular carcinoma cases with serosa invasion. In liver metastasis from colorectal cancer cases with serosa invasion, 18 patients (85.7 %) were detected, and three patients (14.2 %) whose tumors showed complete response to neoadjuvant chemotherapy showed no fluorescence. Both superficial and deep malignant liver tumors were detected with 92.5 % sensitivity. Using 5-ALA-mediated PDD, tumors remaining at the cut surface and postoperative bile leakage were less frequent than in our previous hepatic resections using conventional white-light observation. Moreover, all malignant liver tumors were completely removed with a clear microscopic margin using 5-ALA, with a significant difference in resection margin width between 5-ALA-mediated PDD (6.7 ± 6.9 mm) and white-light observation (9.2 ± 7.0 mm; p = 0.0083). With the detection of malignant liver tumors, residual tumor and bile leakage at the cut surface of the remnant liver were improved by PDD with 5-ALA. This procedure may provide greater sensitivity than the conventional procedure. Furthermore, 5-ALA-mediated PDD can ensure histological clearance regardless of the resection margin and preserve as much liver parenchyma as possible in patients with impaired liver function.

Cellular intrinsic factors involved in the resistance of squamous cell carcinoma to photodynamic therapy.

PubMed

Gilaberte, Yolanda; Milla, Laura; Salazar, Nerea; Vera-Alvarez, Jesús; Kourani, Omar; Damian, Alejandra; Rivarola, Viviana; Roca, Maria José; Espada, Jesús; González, Salvador; Juarranz, Angeles

2014-09-01

Photodynamic therapy (PDT) is widely used to treat non-melanoma skin cancer. However, some patients affected with squamous cell carcinoma (SCC) do not respond adequately to PDT with methyl-δ-aminolevulinic acid (MAL-PDT) and the tumors acquire an infiltrative phenotype and became histologically more aggressive, less differentiated, and more fibroblastic. To search for potential factors implicated in SCC resistance to PDT, we have used the SCC-13 cell line (parental) and resistant SCC-13 cells obtained by repeated MAL-PDT treatments (5th and 10th PDT-resistant generations). Xenografts assays in immunodeficient mice showed that the tumors generated by resistant cells were bigger than those induced by parental cells. Comparative genomic hybridization array (aCGH) showed that the three cell types presented amplicons in 3p12.1 CADM2, 7p11.2 EFGR, and 11q13.3 CCND1 genes. The 5th and 10th PDT-resistant cells showed an amplicon in 5q11.2 MAP3K1, which was not present in parental cells. The changes detected by aCGH on CCND1, EFGR, and MAP3K1 were confirmed in extracts of SCC-13 cells by reverse-transcriptase PCR and by western blot, and by immunohistochemistry in human biopsies from persistent tumors after MAL-PDT. Our data suggest that genomic imbalances related to CCND1, EFGR, and particularly MAP3K1 seem to be involved in the development of the resistance of SCC to PDT.

Biomimetic HDL nanoparticle mediated tumor targeted delivery of indocyanine green for enhanced photodynamic therapy.

PubMed

Wang, Yazhe; Wang, Cheng; Ding, Yang; Li, Jing; Li, Min; Liang, Xiao; Zhou, Jianping; Wang, Wei

2016-12-01

Photodynamic therapy has emerged as a promising strategy for cancer treatment. To ensure the efficient delivery of a photosensitizer to tumor for anticancer effect, a safe and tumor-specific delivery system is highly desirable. Herein, we introduce a novel biomimetic nanoparticle named rHDL/ICG (rHDL/I), by loading amphiphilic near-infrared (NIR) fluorescent dye indocyanine green (ICG) into reconstituted high density lipoproteins (rHDL). In this system, rHDL can mediate photoprotection effect and receptor-guided tumor-targeting transportation of cargos into cells. Upon NIR irradiation, ICG can generate fluorescent imaging signals for diagnosis and monitoring therapeutic activity, and produce singlet oxygen to trigger photodynamic therapy (PDT). Our studies demonstrated that rHDL/I exhibited excellent size and fluorescence stability, light-triggered controlled release feature, and neglectable hemolytic activity. It also showed equivalent NIR response compared to free ICG under laser irradiation. Importantly, the fluorescent signal of ICG loaded in rHDL/I could be visualized subcellularly in vitro and exhibited metabolic distribution in vivo, presenting superior tumor targeting and internalization. This NIR-triggered image-guided nanoparticle produced outstanding therapeutic outcomes against cancer cells, demonstrating great potential of biomimetic delivery vehicles in future clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

Nanoparticle-based photodynamic therapy on non-melanoma skin cancer

NASA Astrophysics Data System (ADS)

Fanjul-Vélez, F.; Arce-Diego, J. L.

2018-02-01

There are several advantages of Photodynamic Therapy (PDT) for nonmelanoma skin cancer treatment compared to conventional treatment techniques such as surgery, radiotherapy or chemotherapy. Among these advantages its noninvasive nature, the use of non ionizing radiation and its high selectivity can be mentioned. Despite all these advantages, the therapeutic efficiency of the current clinical protocol is not complete in all the patients and depends on the type of pathology. An adequate dosimetry is needed in order to personalize the protocol. There are strategies that try to overcome the current PDT shortcomings, such as the improvement of the photosensitizer accumulation in the target tissue, optical radiation distribution optimization or photochemical reactions maximization. These strategies can be further complemented by the use of nanostructures with conventional PDT. Customized dosimetry for nanoparticle-based PDT requires models in order to adjust parameters of different nature to get an optimal tumor removal. In this work, a predictive model of nanoparticle-based PDT is proposed and analyzed. Dosimetry in nanoparticle-based PDT is going to be influenced by photosensitizer-nanoparticle distribution in the malignant tissue, its influence in the optical radiation distribution and the subsequent photochemical reactions. Nanoparticles are considered as photosensitizer carriers on several types of non-melanoma skin cancer. Shielding effects are taken into account. The results allow to compare the estimated treatment outcome with and without nanoparticles.

The application of hyaluronic acid-derivatized carbon nanotubes in hematoporphyrin monomethyl ether-based photodynamic therapy for in vivo and in vitro cancer treatment

PubMed Central

Shi, Jinjin; Ma, Rourou; Wang, Lei; Zhang, Jing; Liu, Ruiyuan; Li, Lulu; Liu, Yan; Hou, Lin; Yu, Xiaoyuan; Gao, Jun; Zhang, Zhenzhong

2013-01-01

Carbon nanotubes (CNTs) have shown great potential in both photothermal therapy and drug delivery. In this study, a CNT derivative, hyaluronic acid-derivatized CNTs (HA-CNTs) with high aqueous solubility, neutral pH, and tumor-targeting activity, were synthesized and characterized, and then a new photodynamic therapy agent, hematoporphyrin monomethyl ether (HMME), was adsorbed onto the functionalized CNTs to develop HMME-HA-CNTs. Tumor growth inhibition was investigated both in vivo and in vitro by a combination of photothermal therapy and photodynamic therapy using HMME-HA-CNTs. The ability of HMME-HA-CNT nanoparticles to combine local specific photodynamic therapy with external near-infrared photothermal therapy significantly improved the therapeutic efficacy of cancer treatment. Compared with photodynamic therapy or photothermal therapy alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy without obvious toxic effects to normal organs. Overall, it was demonstrated that HMME-HA-CNTs could be successfully applied to photodynamic therapy and photothermal therapy simultaneously in future tumor therapy. PMID:23843694

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

Nanoparticle Delivered VEGF-A siRNA Enhances Photodynamic Therapy for Head and Neck Cancer Treatment

PubMed Central

Lecaros, Rumwald Leo G; Huang, Leaf; Lee, Tsai-Chia; Hsu, Yih-Chih

2016-01-01

Photodynamic therapy (PDT) is believed to promote hypoxic conditions to tumor cells leading to overexpression of angiogenic markers such as vascular endothelial growth factor (VEGF). In this study, PDT was combined with lipid–calcium–phosphate nanoparticles (LCP NPs) to deliver VEGF-A small interfering RNA (siVEGF-A) to human head and neck squamous cell carcinoma (HNSCC) xenograft models. VEGF-A were significantly decreased for groups treated with siVEGF-A in human oral squamous cancer cell (HOSCC), SCC4 and SAS models. Cleaved caspase-3 and in situ TdT-mediated dUTP nick-end labeling assay showed more apoptotic cells and reduced Ki-67 expression for treated groups compared to phosphate buffered saline (PBS) group. Indeed, the combined therapy showed significant tumor volume decrease to ~70 and ~120% in SCC4 and SAS models as compared with untreated PBS group, respectively. In vivo toxicity study suggests no toxicity of such LCP NP delivered siVEGF-A. In summary, results suggest that PDT combined with targeted VEGF-A gene therapy could be a potential therapeutic modality to achieve enhanced therapeutic outcome for HNSCC. PMID:26373346

Zinc phthalocyanine-loaded PLGA biodegradable nanoparticles for photodynamic therapy in tumor-bearing mice.

PubMed

Fadel, Maha; Kassab, Kawser; Fadeel, Doa Abdel

2010-03-01

Nanoparticles formulated from the biodegradable copolymer poly(lactic-coglycolic acid) (PLGA) were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting of zinc(II) phthalocyanine (ZnPc) for photodynamic therapy. Three ZnPc nanoparticle formulations were prepared using a solvent emulsion evaporation method and the influence of sonication time on nanoparticle shape, encapsulation and size distribution, in vitro release, and in vivo photodynamic efficiency in tumor-bearing mice were studied. Sonication time did not affect the process yield or encapsulation efficiency, but did affect significantly the particle size. Sonication for 20 min reduced the mean particle size to 374.3 nm and the in vitro release studies demonstrated a controlled release profile of ZnPc. Tumor-bearing mice injected with ZnPc nanoparticles exhibited significantly smaller mean tumor volume, increased tumor growth delay and longer survival compared with the control group and the group injected with free ZnPc during the time course of the experiment. Histopathological examination of tumor from animals treated with PLGA ZnPc showed regression of tumor cells, in contrast to those obtained from animals treated with free ZnPc. The results indicate that ZnPc encapsulated in PLGA nanoparticles is a successful delivery system for improving photodynamic activity in the target tissue.

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

Delta-aminolevulinic acid dehydratase enzyme activity in blood, brain, and liver of lead-dosed ducks

USGS Publications Warehouse

Dieter, M.P.; Finley, M.T.

1979-01-01

Mallard ducks were dosed with a single shotgun pellet (ca. 200 mg lead). After 1 month there was about 1 ppm lead in blood, 2.5 in liver, and 0.5 in brain. Lead-induced inhibition of delta-aminolevulinic acid dehydratase enzyme in blood and cerebellum was much greater than in cerebral hemisphere or liver and was strongly correlated with the lead concentration in these tissues. The cerebellar portion of the brain was more sensitive to delta-aminolevulinic acid dehydratase enzyme inhibition by lead than were the other tissues examined. There was also a greater increase in the glial cell marker enzyme, butyrylcholinesterase, in cerebellum than in cerebral hemisphere, suggesting that nonregenerating neuronal cells were destroyed by lead and replaced by glial cells in that portion of the brain. Even partial loss of cerebellar tissue is severely debilitating in waterfowl, because functions critical to survival such as visual, auditory, motor, and reflex responses are integrated at this brain center.

Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid–induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters

PubMed Central

Roberts, David W.; Valdés, Pablo A.; Harris, Brent T.; Fontaine, Kathryn M.; Hartov, Alexander; Fan, Xiaoyao; Ji, Songbai; Lollis, S. Scott; Pogue, Brian W.; Leblond, Frederic; Tosteson, Tor D.; Wilson, Brian C.; Paulsen, Keith D.

2010-01-01

Object The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection. Methods In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0–3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E–stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0–IV); 2) tumor burden score (0–III); and 3) necrotic burden score (0–III). Results Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of

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

Protoporphyrin IX induced by 5-aminolevulinic acid in bladder cancer cells in voided urine can be extracorporeally quantified using a spectrophotometer.

PubMed

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

2015-06-01

We evaluated the feasibility of photodynamic diagnosis of bladder cancer by spectrophotometric analysis of voided urine samples after extracorporeal treatment with 5-aminolevulinic acid (ALA). Sixty-one patients with bladder cancer, confirmed histologically after the transurethral resection of a bladder tumor, were recruited as the bladder cancer group, and 50 outpatients without history of urothelial carcinoma or cancer-related findings were recruited as the control group. Half of the voided urine sample was incubated with ALA (ALA-treated sample), and the rest was incubated without treatment (ALA-untreated sample). For detecting cellular protoporphyrin IX levels, intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated and ALA-untreated samples at 635 nm was calculated. The differences in the bladder cancer group were significantly greater than those in the control group (p < 0.001). These differences were also significantly greater in patients with high-grade tumors than in those with low-grade tumors (p = 0.004), and also in patients with invasive bladder cancer than in those with noninvasive bladder cancer (p = 0.007). The area under the curve was 0.84. Sensitivity and specificity of the method were 82% and 80%, respectively. We demonstrated that protoporphyrin IX levels in urinary cells treated with ALA could be quantitatively detected by spectrophotometer in patients with bladder cancer. Therefore, this cancer detection system has a potential for clinical use. Copyright © 2015 Elsevier B.V. All rights reserved.

Near-infrared-absorbing gold nanopopcorns with iron oxide cluster core for magnetically amplified photothermal and photodynamic cancer therapy.

PubMed

Bhana, Saheel; Lin, Gan; Wang, Lijia; Starring, Hunter; Mishra, Sanjay R; Liu, Gang; Huang, Xiaohua

2015-06-03

We present the synthesis and application of a new type of dual magnetic and plasmonic nanostructures for magnetic-field-guided drug delivery and combined photothermal and photodynamic cancer therapy. Near-infrared-absorbing gold nanopopcorns containing a self-assembled iron oxide cluster core were prepared via a seed-mediated growth method. The hybrid nanostructures are superparamagnetic and show great photothermal conversion efficiency (η=61%) under near-infrared irradiation. Compact and stable nanocomplexes for photothermal-photodynamic therapy were formed by coating the nanoparticles with near-infrared-absorbing photosensitizer silicon 2,3-naphthalocyannie dihydroxide and stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. The nanocomplex showed enhanced release and cellular uptake of the photosensitizer with the use of a gradient magnetic field. In vitro studies using two different cell lines showed that the dual mode photothermal and photodynamic therapy with the assistance of magnetic-field-guided drug delivery dramatically improved the therapeutic efficacy of cancer cells as compared to the combination treatment without using a magnetic field and the two treatments alone. The "three-in-one" nanocomplex has the potential to carry therapeutic agents deep into a tumor through magnetic manipulation and to completely eradicate tumors by subsequent photothermal and photodynamic therapies without systemic toxicity.

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.

In vivo 808 nm image-guided photodynamic therapy based on an upconversion theranostic nanoplatform.

PubMed

Liu, Xiaomin; Que, Ivo; Kong, Xianggui; Zhang, Youlin; Tu, Langping; Chang, Yulei; Wang, Tong Tong; Chan, Alan; Löwik, Clemens W G M; Zhang, Hong

2015-09-28

A new strategy for efficient in vivo image-guided photodynamic therapy (PDT) has been demonstrated utilizing a ligand-exchange constructed upconversion-C60 nanophotosensitizer. This theranostic platform is superior to the currently reported nanophotosensitizers in (i) directly bonding photosensitizer C60 to the surface of upconversion nanoparticles (UCNPs) by a smart ligand-exchange strategy, which greatly shortened the energy transfer distance and enhanced the (1)O2 production, resulting in the improvement of the therapeutic effect; (ii) realizing in vivo NIR 808 nm image-guided PDT with both excitation (980 nm) and emission (808 nm) light falling in the biological window of tissues, which minimized auto-fluorescence, reduced light scatting and improved the imaging contrast and depth, and thus guaranteed noninvasive diagnostic accuracy. In vivo and ex vivo tests demonstrated its favorable bio-distribution, tumor-selectivity and high therapeutic efficacy. Owing to the effective ligand exchange strategy and the excellent intrinsic photophysical properties of C60, (1)O2 production yield was improved, suggesting that a low 980 nm irradiation dosage (351 J cm(-2)) and a short treatment time (15 min) were sufficient to perform NIR (980 nm) to NIR (808 nm) image-guided PDT. Our work enriches the understanding of UCNP-based PDT nanophotosensitizers and highlights their potential use in future NIR image-guided noninvasive deep cancer therapy.

Acidity-Triggered Tumor Retention/Internalization of Chimeric Peptide for Enhanced Photodynamic Therapy and Real-Time Monitoring of Therapeutic Effects.

PubMed

Han, Kai; Zhang, Wei-Yun; Ma, Zhao-Yu; Wang, Shi-Bo; Xu, Lu-Ming; Liu, Jia; Zhang, Xian-Zheng; Han, He-You

2017-05-17

Photodynamic therapy (PDT) holds great promise in tumor treatment. Nevertheless, it remains highly desirable to develop easy-to-fabricated PDT systems with improved tumor accumulation/internalization and timely therapeutic feedback. Here, we report a tumor-acidity-responsive chimeric peptide for enhanced PDT and noninvasive real-time apoptosis imaging. Both in vitro and in vivo studies revealed that a tumor mildly acidic microenvironment could trigger rapid protonation of carboxylate anions in chimeric peptide, which led to increased ζ potential, improved hydrophobicity, controlled size enlargement, and precise morphology switching from sphere to spherocylinder shape of the chimeric peptide. All of these factors realized superfast accumulation and prolonged retention in the tumor region, selective cellular internalization, and enhanced PDT against the tumor. Meanwhile, this chimeric peptide could further generate reactive oxygen species and initiate cell apoptosis during PDT. The subsequent formation of caspase-3 enzyme hydrolyzed the chimeric peptide, achieving a high signal/noise ratio and timely fluorescence feedback. Importantly, direct utilization of the acidity responsiveness of a biofunctional Asp-Glu-Val-Asp-Gly (DEVDG, caspase-3 enzyme substrate) peptide sequence dramatically simplified the preparation and increased the performance of the chimeric peptide furthest.

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.

The efficacy and tolerability of 5-aminolevulinic acid 5% thermosetting gel photodynamic therapy (PDT) in the treatment of mild-to-moderate acne vulgaris. A two-center, prospective assessor-blinded, proof-of-concept study.

PubMed

Serini, Stefano Maria; Cannizzaro, Maria Vittoria; Dattola, Annunziata; Garofalo, Virginia; Del Duca, Esther; Ventura, Alessandra; Milani, Massimo; Campione, Elena; Bianchi, Luca

2018-05-22

Acne vulgaris is a chronic inflammatory skin disease, commonly treated with topical or systemic drugs, according to the severity of the condition. Retinoids and antibiotic compounds are considered cornerstone approaches in this condition. However, low adherence to the therapy and the issue of bacterial resistance undermine the efficacy in the long term. Photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA) has shown to be effective in the treatment of inflammatory acne. Skin tolerability, however, could be a limiting factor for a widespread use of this approach. A new formulation of 5% ALA in thermosetting gel has been recently available. This formulation allows a more convenient application procedure without occlusion and better and more efficient release of the active compound in comparison with traditional ALA formulations like creams or ointments. To evaluate in a two-center, assessor-blinded, prospective, proof-of-concept study, the efficacy, and tolerability of red-light (630 nm) PDT with a new 5-ALA "low-dose" topical gel formulation (5%) in the treatment of inflammatory mild-to-moderate acne vulgaris (AV). A total of 35 subjects with moderate AV of the face (mean age: 24 ± 8 years, 13 men and 22 women) were enrolled, after their written informed consent. The primary outcome was the evolution of GAG (Global Acne Grade System) score at baseline and after an average of three, 630-nm, 15-minute, PDT sessions, performed every 2 weeks. GAG score was also calculated in a follow-up visit 6 months after the last PDT session. Skin tolerability was assessed during PDT sessions with a patient-reported discomfort level evaluation score from 0 (no discomfort at all) to 3 (severe discomfort). At baseline, the GAG score was 21 ± 6. After the last PDT session, the GAG score evaluated in a blinded fashion (digital photographs) was significantly reduced to 6.5 ± 5.7, representing a 70% reduction (P = .0001, Wilcoxon test; mean difference 14.9; 95% CI of

Enhanced Photodynamic Therapy by Reduced Levels of Intracellular Glutathione Obtained By Employing a Nano-MOF with CuII as the Active Center.

PubMed

Zhang, Wei; Lu, Jun; Gao, Xiaonan; Li, Ping; Zhang, Wen; Ma, Yu; Wang, Hui; Tang, Bo

2018-02-16

In photodynamic therapy (PDT), the level of reactive oxygen species (ROS) produced in the cell directly determines the therapeutic effect. Improvement in ROS concentration can be realized by reducing the glutathione (GSH) level or increasing the amount of photosensitizer. However, excessive amounts photosensitizer may cause side effects. Therefore, the development of photosensitizers that reduce GSH levels through synergistically improving ROS concentration in order to strengthen the efficacy of PDT for tumor is important. We report a nano-metal-organic framework (Cu II -metalated nano-MOF {CuL-[AlOH] 2 } n (MOF-2, H 6 L=mesotetrakis(4-carboxylphenyl)porphyrin)) based on Cu II as the active center for PDT. This MOF-2 is readily taken up by breast cancer cells, and high levels of ROS are generated under light irradiation. Meanwhile, intracellular GSH is considerably decreased owing to absorption on MOF-2; this synergistically increases ROS concentration and accelerates apoptosis, thereby enhancing the effect of PDT. Notably, based on the direct adsorption of GSH, MOF-2 showed a comparable effect with the commercial antitumor drug camptothecin in a mouse breast cancer model. This work provides strong evidence for MOF-2 as a promising new PDT candidate and anticancer drug. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy

PubMed Central

Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

2017-01-01

Background Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine—Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Methods Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. Results GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)—related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Conclusions Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. General significance Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy. PMID:28278159

Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy.

PubMed

Tudor, Diana; Nenu, Iuliana; Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

2017-01-01

Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.

Photodynamic therapy for recurrent respiratory papillomatosis.

PubMed

Lieder, Anja; Khan, Muhammad K; Lippert, Burkard M

2014-06-05

Recurrent respiratory papillomatosis (RRP) is a benign condition of the mucosa of the upper aerodigestive tract. It is characterised by recurrent papillomatous lesions and is associated with human papillomavirus (HPV). Frequent recurrence and rapid papilloma growth are common and in part responsible for the onset of potentially life-threatening symptoms. Most patients afflicted by the condition will require repeated surgical treatments to maintain their airway, and these may result in scarring and voice problems. Photodynamic therapy introduces a light-sensitising agent, which is administered either orally or by injection. This substance (called a photo-sensitiser) is selectively retained in hyperplastic and neoplastic tissue, including papilloma. It is then activated by light of a specific wavelength and may be used as a sole or adjuvant treatment for RRP. To assess the effects of photodynamic therapy in the management of recurrent respiratory papillomatosis (RRP) in children and adults. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 27 January 2014. Randomised controlled trials utilising photodynamic therapy as sole or adjuvant therapy in participants of any age with proven RRP versus control intervention. Primary outcome measures were symptom improvement (respiratory distress/dyspnoea and voice quality), quality of life improvement and recurrence-free interval. Secondary outcomes included reduction in the frequency of surgical intervention, reduction in disease volume and adverse effects of treatment.   We used the standard methodological procedures expected by The Cochrane Collaboration. Meta-analysis was not possible and results are presented descriptively. We included one trial with a total of 23

Two-photon excitation of porphyrin-functionalized porous silicon nanoparticles for photodynamic therapy.

PubMed

Secret, Emilie; Maynadier, Marie; Gallud, Audrey; Chaix, Arnaud; Bouffard, Elise; Gary-Bobo, Magali; Marcotte, Nathalie; Mongin, Olivier; El Cheikh, Khaled; Hugues, Vincent; Auffan, Mélanie; Frochot, Céline; Morère, Alain; Maillard, Philippe; Blanchard-Desce, Mireille; Sailor, Michael J; Garcia, Marcel; Durand, Jean-Olivier; Cunin, Frédérique

2014-12-03

Porous silicon nanoparticles (pSiNPs) act as a sensitizer for the 2-photon excitation of a pendant porphyrin using NIR laser light, for imaging and photodynamic therapy. Mannose-functionalized pSiNPs can be vectorized to MCF-7 human breast cancer cells through a mannose receptor-mediated endocytosis mechanism to provide a 3-fold enhancement of the 2-photon PDT effect. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Photodynamic therapy: new treatment for recalcitrant Malassezia folliculitis.

PubMed

Lee, Jin Woong; Kim, Beom Joon; Kim, Myeung Nam

2010-02-01

Malassezia folliculitis commonly has been treated with oral antifungal medications. However, it has many therapeutic weaknesses such as infection relapse, drug resistance, or adverse effects like hepatotoxicity and gastrointestinal discomfort. Hence, there remains an ongoing need for alternative treatments for recalcitrant Malassezia folliculitis. Recently, many dermatologists suggest photodynamic therapy (PDT) as an alternative therapeutic option for its antimicrobial effect. To investigate the efficacy of methyl 5-aminolevulinic acid (MAL)-PDT for the treatment of recalcitrant Malassezia folliculitis. Six Korean patients aged 23-47 years with recalcitrant Malassezia folliculitis were enrolled in this study. The patients enrolled in this study either refused oral medication or were unable to take oral antifungal agents due to hepatotoxicity concerns. Thus, we offered these patients MAL-PDT as an alternative treatment option. For all patients, photographs of the lesion(s) were taken prior to initiating treatment. MAL cream (Metvix, Galderma, France) was applied to each lesion (located on the patients' trunks) and covered with an adhesive occlusive dressing polyurethane film (Tegaderm, 3M Healthcare, St. Paul, MN). After 3 hours, the cream was wiped off and illumination was performed immediately thereafter with non-coherent red light using light-emitting diodes (Aktilite lamp, PhotoCure, Oslo, Norway, average wavelength 630 nm, light dose 37 J/cm(2)). Illumination was performed for 7.5 minutes. Patients underwent totally three sessions of MAL-PDT at 2-week intervals. One month after the last PDT treatment, patients returned to the hospital and lesions were photographed. After three sessions of MAL-PDT, inflammatory lesions had decreased and improved obviously in four patients, had improved slightly in one patient, and had not improved in one patient. MAL-PDT may be an effective treatment option for patients with recalcitrant Malassezia folliculitis. However, the

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

PubMed

Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

2010-01-25

Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

Mechanism of photodynamic inactivation of hepatocarcinoma cells with sulfonated aluminum phthalocyanine

NASA Astrophysics Data System (ADS)

Yu, Hong-Yu; Dong, Rong-Chun; Chen, Ji-Yao; Cai, Huai-Xin

1993-03-01

The mechanism of photodynamic therapy (PDT) with sulfonated aluminum phthalocyanine (AlSPC) studied with the human hepatocellular carcinoma cell line in culture is reported herein. Photofrin II (PII) was chosen as the control photosensitizer of AlSPC. Deuterium oxide (D2O), an enhancer of singlet oxygen (1O2); 1,3-diphenylisobenzofuran (DPBF), a quencher of 1O2: glycerol, a quencher of OH radical (OH(DOT)); superoxide dismutase (SOD), a quencher of O2- radical (O2-(DOT)); diethyldithiocarbamate (DDC), an inhibitor of SOD and glutathione peroxidase; were introduced into both the processes of photodynamic inactivation of human liver cancer cells in culture with AlSPC (AlSPC-PDT) and with PII (PII-PDT). The results suggest that: 1O2 is dominantly involved in both PII-PDT and AlSPC-PDT; O2-(DOT) is involved in AlSPC-PDT in a lower degree than 1O2, while almost not involved in PII-PDT; OH(DOT) is involved in PII-PDT in a lower degree than 1O2, while almost not involved in AlSPC-PDT.

The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.

PubMed Central

Lilge, L.; Olivo, M. C.; Schatz, S. W.; MaGuire, J. A.; Patterson, M. S.; Wilson, B. C.

1996-01-01

The applicability and limitations of a photodynamic threshold model, used to describe quantitatively the in vivo response of tissues to photodynamic therapy, are currently being investigated in a variety of normal and malignant tumour tissues. The model states that tissue necrosis occurs when the number of photons absorbed by the photosensitiser per unit tissue volume exceeds a threshold. New Zealand White rabbits were sensitised with porphyrin-based photosensitisers. Normal brain or intracranially implanted VX2 tumours were illuminated via an optical fibre placed into the tissue at craniotomy. The light fluence distribution in the tissue was measured by multiple interstitial optical fibre detectors. The tissue concentration of the photosensitiser was determined post mortem by absorption spectroscopy. The derived photodynamic threshold values for normal brain are significantly lower than for VX2 tumour for all photosensitisers examined. Neuronal damage is evident beyond the zone of frank necrosis. For Photofrin the threshold decreases with time delay between photosensitiser administration and light treatment. No significant difference in threshold is found between Photofrin and haematoporphyrin derivative. The threshold in normal brain (grey matter) is lowest for sensitisation by 5 delta-aminolaevulinic acid. The results confirm the very high sensitivity of normal brain to porphyrin photodynamic therapy and show the importance of in situ light fluence monitoring during photodynamic irradiation. Images Figure 1 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8562339

A Review of Progress in Clinical Photodynamic Therapy

PubMed Central

Huang, Zheng

2005-01-01

Photodynamic therapy (PDT) has received increased attention since the regulatory approvals have been granted to several photosensitizing drugs and light applicators world-wide. Much progress has been seen in basic sciences and clinical photodynamics in recent years. This review will focus on new developments of clinical investigation and discuss the usefulness of various forms of PDT techniques for curative or palliative treatment of malignant and non-malignant diseases. PMID:15896084

Photodynamic therapy in actinic cheilitis: clinical and anatomopathological evaluation of 19 patients.

PubMed

Ribeiro, Camila Ferrari; Souza, Fernanda Homem de Mello de; Jordão, Juliana Merheb; Haendchen, Letícia Cortes; Mesquita, Lismary; Schmitt, Juliano Vilaverde; Faucz, Luciana Lisboa

2012-01-01

Actinic cheilitis, a common disease caused by chronic solar exposure and tobacco use, is considered a premalignant lesion with potential to develop into squamous cell carcinoma. Some of the available treatments are invasive, have unaesthetic results and require multiple sessions. To assess the efficacy of a therapy and its cosmetic results. In this uncontrolled clinical trial a single photodynamic therapy (PDT) session using 16% methyl-aminolevulinate was performed on actinic cheilitis of the lower lip. A standardized questionnaire was applied in order to assess the clinical improvement from the patients' point of view and the satisfaction with the treatment. Anatomopathological evaluation was performed before the treatment and two months afterwards. The sample was composed of 19 patients (10 males and 9 females), phototypes I to III, with average age of 62 years. Main adverse effects were: sudden pain, scabs, herpes flare-up, and edema. The average score of pain during the procedure was 5,8+2,9. At the final assessment the patients reported improvement of 80% and satisfaction of 85% (p<0.01). Anatomopathological analysis showed a significant decrease of dysplasia (p=0.03) in spite of its presence in 84% of cases. There was no significant correlation between the level of dysplasia with either the subjective impression of clinical improvement (p=0.82) or with the patients' final satisfaction (p=0.96). PDT is effective in the treatment of actinic cheilitis, but it is associated with a significant level of pain. Due to the persistence of dysplasia, more research needs to be done in order to define the ideal number of sessions for the effective treatment of these lesions.

The proton-coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5-aminolevulinic acid.

PubMed

Xie, Yehua; Hu, Yongjun; Smith, David E

2016-01-01

5-Aminolevulinic acid (5-ALA) has been widely used in photodynamic therapy and immunofluorescence of tumours. In the present study, the intestinal permeability and oral pharmacokinetics of 5-ALA were evaluated to probe the contribution of the proton-coupled oligopeptide transporter 1 (PEPT1) to the oral absorption and systemic exposure of this substrate. In situ single-pass intestinal perfusions and in vivo oral pharmacokinetic studies were performed in wildtype and Pept1 knockout mice. Perfusion studies were performed as a function of concentration dependence, specificity and permeability of 5-ALA in different intestinal segments. Pharmacokinetic studies were performed after 0.2 and 2.0 μmoL·g(-1) doses of 5-ALA. The permeability of 5-ALA was substantial in duodenal, jejunal and ileal regions of wildtype mice, but the residual permeability of 5-ALA in the small intestine from Pept1 knockout mice was only about 10% of that in wildtype animals. The permeability of 5-ALA in jejunum was specific for PEPT1 with no apparent contribution of other transporters, including the proton-coupled amino acid transporter 1 (PAT1). After oral dosing, the systemic exposure of 5-ALA was reduced by about twofold during PEPT1 ablation, and the pharmacokinetics were dose-proportional after the 0.2 and 2.0 µmol·g(-1) doses. PEPT1 had a minor effect on the disposition and peripheral tissue distribution of 5-ALA. Our findings suggested a major role of PEPT1 in the intestinal permeability and oral absorption of 5-ALA. In contrast, another proton-coupled transporter, PAT1, appeared to play a limited role, at best. © 2015 The British Pharmacological Society.

Influence of protoporphyrin IX loaded phloroglucinol succinic acid dendrimer in photodynamic therapy

NASA Astrophysics Data System (ADS)

Kumar, M. Suresh; Aruna, P.; Ganesan, S.

2018-03-01

One of the major problems reported clinically for photosensitizers (PS) in Photodynamic therapy (PDT) is, the cause of side-effects to normal tissue due to dark toxicity. The usefulness of photosensitizers can be made possible by reducing its dark toxicity nature. In such scenario, biocompatible carriers can be used as a drug delivery system to evade the problems that arises while using free (dark toxic) drugs. So in this study, we have developed a nano drug delivery system called Phloroglucinol Succinic acid (PGSA) dendrimer, entrapped a photosensitizer, protoporphyrin IX (PpIX) inside the system and investigated whether the photodynamic efficacy of the anionic surface charged dendrimer-PpIX nano formulation is enhanced than achieved by the free PpIX in HeLa cancer cell lines. Moreover, the Reactive oxygen species (ROS) production was monitored using 2‧,7‧-dichlorodihydrofluorescein diacetate (H2DCF-DA)- ROS Marker with phase contrast microscopy for the IC50 values of free and dendrimer-PpIX nano formulation. Similarly, the mode of cell death has been confirmed by cell cycle analysis for the same. For the in vitro PDT application, we have used a simple light source (Light Emitting Diode) with a power of 30-50 mW for 20 min irradiation. Hence, in this study we have taken steps to report this anionic drug delivery system is good to consider for the photodynamic therapy applications with the photosensitizer, PpIX which satisfied the prime requirement of PDT.

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

Photodynamic activity of natural anthraquinones on fibroblasts

NASA Astrophysics Data System (ADS)

Dimmer, Jesica; Ramos Silva, Camila; Núñez Montoya, Susana C.; Cabrera, José Luis; Ribeiro, Martha S.

2018-02-01

Natural anthraquinones (AQs) isolated from Heterophyllaea lycioides (Rusby) Sandwith (Rubiaceae) demonstrated to have photodynamic properties: soranjididol (Sor), 5-Chlorosoranjidiol (5-ClSor), bisoranjidiol (Bisor), 7-Chlorobisoranjidiol (7-ClBisor) and lycionine (Lyc). Sor, 5-ClSor and Bisor exhibited photodynamic inactivation on bacteria and parasites. As they could be used in topical application, the aim of this work was to study their photodynamic activity on fibroblasts. AQs were tested at 2.5 μM in darkness and under irradiation conditions. They were photoactivated with violet-blue LED (λ = 410 +/- 10 nm; fluence rate =50 mW/cm2) and exposure time corresponded to a fluence of 27 J/cm2. Negative and positive control (-C and +C, respectively) were included. Mitochondrial activity was determined by using MTT assay that is a measure of the cell viability and it was expressed as a percentage respect to -C (% CV). Results showed that AQs in darkness conditions showed similar metabolic activity as -C, except for 5-ClSor (about 75% CV). Under irradiation, AQs exhibited dissimilar results. Sor and 7-ClBisor maintained cell viability at approximately 100%, Bisor and Lyc around 70%, whereas 5-ClSor reduced cell viability by 90%. Taken together, our results suggest that Sor could mediate photodynamic therapy (PDT) in cutaneous infections since no toxicity was observed in fibroblasts. On the other hand, 5-ClSor could be used for topical PDT of keloids and hypertrophic scars.

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.

Mitochondria-targeting for improved photodynamic therapy

NASA Astrophysics Data System (ADS)

Ngen, Ethel J.

, other strategies to target mitochondria for improved photodynamic activity were investigated. In a continuing project, we evaluated the ability of delocalized lipophilic cationic dyes to deliver photosensitizers to mitochondria by exploiting the membrane potential difference between the cytoplasm and mitochondria. Two conjugates: a porphyrin--rhodamine B conjugate (TPP--Rh) and a porphyrin-acridine orange conjugate (TPP--AO), each possessing a single delocalized lipophilic cation, were designed and synthesized. The conjugates were synthesized by conjugating a monohydroxy porphyrin (TPP-OH) to rhodamine B (Rh B) and acridine orange base (AO), respectively, via saturated hydrocarbon linkers. To evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro photodynamic activities were studied in comparison to those of TPP-OH, the parent porphyrin photosensitizer. Although fluorescence energy transfer (FRET) was observed in the conjugates, they were capable of generating singlet oxygen at rates comparable to TPP-OH. In a final project, we evaluated the photophysical potential of TPP-Rh to act as a two-photon photosensitizer for PDT. Two-photon PDT is a rational approach used to improve light penetration through the skin. Rhodamine B is an effective two-photon chromophore and could significantly improve the two-photon absorption of the porphyrin photosensitizer in the TPP-Rh dyad system following energy transfer. Thus the porphyrin--rhodamine B dyad (TPP--Rh), previously demonstrated to preferentially accumulate in the mitochondria, was photophysically evaluated as a potential two-photon photosensitizer. To evaluate the efficiency of TPP-Rh as a two-photon photosensitizer, its two-photon photophysical properties were compared with those of its individual components (Rh B and TPP-OH). This included: the two-photon cross sections (sigma 2), RET kinetics and dynamics and rates of singlet oxygen generation. A FRET efficiency of ~99

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

Tumor Uptake And Photodynamic Activity Of Sulfonated Metallo Phthalocyanines

NASA Astrophysics Data System (ADS)

van Lier, Johan E.; Rousseau, Jacques; Paquette, Benoit; Brasseur, N.; Langlois, Rejean; Ali, Hasrat

1989-06-01

Sulfonated metallo phthalocyanines (M-SPC) are extensively studied as sensitizers for photodynamic therapy of cancer. They strongly absorb clinically useful red light with absorption maxima between 670-680 nm. Their photodynamic properties depend on the nature of the central metal ion as well as the degree of substitution on the macrocycle. The zinc, aluminum and gallium complexes are efficient photo-generators of singlet oxygen, the species most likely responsible for their phototoxicity and tumoricidal action. Tissue distribution pattern, cell penetration and dye aggregation are strongly affected by the degree of sulfonation of the dyes. Mono- and disulfonated M-SPC have the highest tendency to form photo-inactive aggregates. However, these lower sulfonated dyes more readily cross cell membranes resulting, in vitro, in enhanced phototoxicity. In vivo, the highly sulfonated hydrophilic M-SPC show the best tumor localization properties but the lower sulfonated dyes still exhibit the best photo-activity. Variations in activities between the differently sulfonated M-SPC are far less pronounced in vivo as compared to in vitro conditions. Such discrepancies are explained by the combined action of numerous vectors including interaction of M-SPC with plasma proteins, vascular versus cellular photo-damage, tumor retention, cell penetration as well as the degree of aggregation of the dye.

Photodynamic therapy for the treatment of folliculitis decalvans.

PubMed

Castaño-Suárez, Esther; Romero-Maté, Alberto; Arias-Palomo, Dolores; Borbujo, Jesús

2012-04-01

Folliculitis decalvans is a chronic form of deep folliculitis that occurs on the scalp as patches of scarring alopecia at the expanding margins of which are follicular pustules. Treatment of folliculitis decalvans is extremely difficult with a resultant poor prognosis. Photodynamic therapy has been reported to be effective in disorders as acne or folliculitis. We report one patient with folliculitis decalvans who was successfully treated with photodynamic therapy. © 2012 John Wiley & Sons A/S.

Cell Death Pathways and Phthalocyanine as an Efficient Agent for Photodynamic Cancer Therapy

PubMed Central

Mfouo-Tynga, Ivan; Abrahamse, Heidi

2015-01-01

The mechanisms of cell death can be predetermined (programmed) or not and categorized into apoptotic, autophagic and necrotic pathways. The process of Hayflick limits completes the execution of death-related mechanisms. Reactive oxygen species (ROS) are associated with oxidative stress and subsequent cytodamage by oxidizing and degrading cell components. ROS are also involved in immune responses, where they stabilize and activate both hypoxia-inducible factors and phagocytic effectors. ROS production and presence enhance cytodamage and photodynamic-induced cell death. Photodynamic cancer therapy (PDT) uses non-toxic chemotherapeutic agents, photosensitizer (PS), to initiate a light-dependent and ROS-related cell death. Phthalocyanines (PCs) are third generation and stable PSs with improved photochemical abilities. They are effective inducers of cell death in various neoplastic models. The metallated PCs localize in critical cellular organelles and are better inducers of cell death than other previous generation PSs as they favor mainly apoptotic cell death events. PMID:25955645

A Bifunctional Photosensitizer for Enhanced Fractional Photodynamic Therapy: Singlet Oxygen Generation in the Presence and Absence of Light.

PubMed

Turan, Ilke Simsek; Yildiz, Deniz; Turksoy, Abdurrahman; Gunaydin, Gurcan; Akkaya, Engin U

2016-02-18

The photosensitized generation of singlet oxygen within tumor tissues during photodynamic therapy (PDT) is self-limiting, as the already low oxygen concentrations within tumors is further diminished during the process. In certain applications, to minimize photoinduced hypoxia the light is introduced intermittently (fractional PDT) to allow time for the replenishment of cellular oxygen. This condition extends the time required for effective therapy. Herein, we demonstrated that a photosensitizer with an additional 2-pyridone module for trapping singlet oxygen would be useful in fractional PDT. Thus, in the light cycle, the endoperoxide of 2-pyridone is generated along with singlet oxygen. In the dark cycle, the endoperoxide undergoes thermal cycloreversion to produce singlet oxygen, regenerating the 2-pyridone module. As a result, the photodynamic process can continue in the dark as well as in the light cycles. Cell-culture studies validated this working principle in vitro. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Skin tumor development after UV irradiation and photodynamic therapy is unaffected by short-term pretreatment with 5-fluorouracil, imiquimod and calcipotriol. An experimental hairless mouse study.

PubMed

Bay, Christiane; Togsverd-Bo, Katrine; Lerche, Catharina M; Haedersdal, Merete

2016-01-01

Photodynamic therapy (PDT) delays ultraviolet (UV) radiation-induced squamous cell carcinomas (SCCs) in hairless mice. Efficacy may be enhanced by combining PDT with antineoplastic or pro-differentiating agents. We investigated if pretreatment with 5-fluorouracil (5FU), imiquimod (IMIQ) or calcipotriol (CAL) before PDT further delays tumor onset. Hairless mice (n=224) were exposed 3 times weekly to 3 standard erythema doses (SED) of UV radiation. Methyl-aminolevulinate (MAL)-PDT sessions were given on days 45 and 90 before SCC development. Three applications of topical 5FU, IMIQ or CAL were given before each PDT session. Fluorescence photography quantified protoporphyrin IX (PpIX) formation. PDT delayed UV-induced SCC development by 59 days (212 days UV-MAL-PDT vs. 153 days UV-control, P<0.001). Pretreatment with 5FU, IMIQ or CAL before PDT did not further delay SCC onset compared to PDT alone (207 days UV-5FU-MAL-PDT, 215 days UV-IMIQ-MAL-PDT, 206 days UV-CAL-MAL-PDT vs. 212 days UV-MAL-PDT, P=ns). PpIX fluorescence intensified by 5FU-pretreatment (median 21,392 au UV-5FU-MAL-PDT, P=0.011), decreased after IMIQ-pretreatment (12,452 au UV-IMIQ-MAL-PDT, P<0.001), and was unaffected by CAL-pretreatment (19,567 au UV-CAL-MAL-PDT, P=ns) compared to MAL alone (18,083 au UV-MAL-PDT). Short-term three-day pretreatment with 5FU, IMIQ and CAL before PDT does not further delay tumor onset in UV-exposed hairless mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Investigation of photodynamic effect caused by MPPa-PDT on breast cancer Investigation of photodynamic effect caused by MPPa-PDT

NASA Astrophysics Data System (ADS)

Tian, Y. Y.; Hu, X. Y.; Leung, W. N.; Yuan, H. Q.; Zhang, L. Y.; Cui, F. A.; Tian, X.

2012-10-01

Breast cancer is the common malignant tumor, the incidence increases with age. Photodynamic therapy (PDT) is a new technique applied in tumors, which involves the administration of a tumor localizing photosensitizer and it is followed by the activation of a specific wavelength. Pyropheophorbide-a methyl ester (MPPa), a derivative of chlorophyll, is a novel potent photosensitizer. We are exploring the photodynamic effect caused by MPPa-PDT on breast cancer. The in vitro and in vivo experiments indicate that MPPa is a comparatively ideal photosensitizer which can induce apoptosis in breast cancer.

Photodynamic injury of isolated crayfish neuron and surrounding glial cells: the role of p53

NASA Astrophysics Data System (ADS)

Sharifulina, S. A.; Uzdensky, A. B.

2015-03-01

The pro-apoptotic transcription factor p53 is involved in cell responses to injurious impacts. Using its inhibitor pifithrin- α and activators tenovin-1, RITA and WR-1065, we studied its potential participation in inactivation and death of isolated crayfish mechanoreceptor neuron and satellite glial cells induced by photodynamic treatment, a strong inducer of oxidative stress. In dark, p53 activation by tenovin-1 or WR-1065 shortened activity of isolated neurons. Tenovin-1 and WR-1065 induced apoptosis of glial cells, whereas pifithrin-α was anti-apoptotic. Therefore, p53 mediated glial apoptosis and suppression of neuronal activity after axotomy. Tenovin-1 but not other p53 modulators induced necrosis of axotomized neurons and surrounding glia, possibly, through p53-independent pathway. Under photodynamic treatment, p53 activators tenovin-1 and RITA enhanced glial apoptosis indicating the pro-apoptotic activity of p53. Photoinduced necrosis of neurons and glia was suppressed by tenovin-1 and, paradoxically, by pifithrin-α. Modulation of photoinduced changes in the neuronal activity and necrosis of neurons and glia was possibly p53-independent. The different effects of p53 modulators on neuronal and glial responses to axotomy and photodynamic impact were apparently associated with different signaling pathways in neurons and glial cells.

Preclinical studies of photodynamic therapy of intracranial tissues

NASA Astrophysics Data System (ADS)

Lilge, Lothar D.; Sepers, Marja; Park, Jane; O'Carroll, Cindy; Pournazari, Poupak; Prosper, Joe; Wilson, Brian C.

1997-05-01

The applicability and limitations of the photodynamic threshold model were investigated for an intracranial tumor (VX2) and normal brain tissues in a rabbit model. Photodynamic threshold values for four different photosensitizers, i.e., Photofrin, 5(delta) -aminolaevulinic acid (5(delta) -ALA) induced Protoporphyrin IX (PPIX), Tin Ethyl Etiopurpurin (SnET2), and chloroaluminum phthalocyanine (AlClPc), were determined based on measured light fluence distributions, macroscopic photosensitizer concentration in various brain structures, and histologically determined extent of tissue necrosis following PDT. For Photofrin, AlClPc, and SnET2, normal brain displayed a significantly lower threshold value than VX2 tumor. For 5(delta) -ALA induced PPIX and SnET2 no or very little white matter damage, equalling to very high or infinite threshold values, was observed. Additionally, the latter two photosensitizers showed significantly lower uptake in white matter compared to other brain structures and VX2 tumor. Normal brain structures lacking a blood- brain-barrier, such as the choroid plexus and the meninges, showed high photosensitizer uptake for all photosensitizers, and, hence, are at risk when exposed to light. Results to date suggest that the photodynamic threshold values iares valid for white matter, cortex and VX2 tumor. For clinical PDT of intracranial neoplasms 5(delta) -ALA induced PPIX and SnET2 appear to be the most promising for selective tumor necrosis.However, the photosensitizer concentration in each normal brain structure and the fluence distribution throughout the treatment volume and adjacent tissues at risk must be monitored to maximize the selectivity of PDT for intracranial tumors.

Cancer cell membrane-coated magnetic nanoparticles for MR/NIR fluorescence dual-modal imaging and photodynamic therapy.

PubMed

Li, Jiong; Wang, Xuandong; Zheng, Dongye; Lin, Xinyi; Wei, Zuwu; Zhang, Da; Li, Zhuanfang; Zhang, Yun; Wu, Ming; Liu, Xiaolong

2018-05-22

Theranostic nanoprobes integrated with dual-modal imaging and therapeutic functions, such as photodynamic therapy (PDT), have exhibited significant potency in cancer treatments due to their high imaging accuracy and non-invasive advantages for cancer elimination. However, biocompatibility and highly efficient accumulation of these nanoprobes in tumor are still unsatisfactory for clinical application. In this study, a photosensitizer -loaded magnetic nanobead with surface further coated with a layer of cancer cell membrane (SSAP-Ce6@CCM) was designed to improve the biocompatibility and cellular uptake and ultimately achieve enhanced MR/NIR fluorescence imaging and PDT efficacy. Compared with similar nanobeads without CCM coating, SSAP-Ce6@CCM showed significantly enhanced cellular uptake, as evidenced by Prussian blue staining, confocal laser scanning microscopy (CLSM) and flow cytometric analysis. Consequently, SSAP-Ce6@CCM displayed a more distinct MR/NIR imaging ability and more obvious photo-cytotoxicity towards cancer cells under 670 nm laser irradiation. Furthermore, the enhanced PDT effect benefited from the surface coating of cancer cell membrane was demonstrated in SMMC-7721 tumor-bearing mice through tumor growth observation and tumor tissue pathological examination. Therefore, this CCM-disguised nanobead that integrated the abilities of MR/NIR fluorescence dual-modal imaging and photodynamic therapy might be a promising theranostic platform for tumor treatment.

Use of wood vinegar to enhance 5-aminolevulinic acid production by selected Rhodopseudomonas palustris in rubber sheet wastewater for agricultural use.

PubMed

Nunkaew, Tomorn; Kantachote, Duangporn; Chaiprapat, Sumate; Nitoda, Teruhiko; Kanzaki, Hiroshi

2018-05-01

This study aimed to produce inexpensive 5-aminolevulinic acid (ALA) in a non-sterile latex rubber sheet wastewater (RSW) by Rhodopseudomonas palustris TN114 and PP803 for the possibility to use in agricultural purposes by investigating the optimum conditions, and applying of wood vinegar (WV) as an economical source of levulinic acid to enhance ALA content. The Box-Behnken Design experiment was conducted under microaerobic-light conditions for 96 h with TN114, PP803 and their mixed culture (1:1) by varying initial pH, inoculum size (% v/v) and initial chemical oxygen demand (COD, mg/L). Results showed that the optimal condition (pH, % inoculum size, COD) of each set to produce extracellular ALA was found at 7.50, 6.00, 2000 for TN114; 7.50, 7.00, 3000 for PP803; and 7.50, 6.00, 4000 for a mixed culture; and each set achieved COD reduction as high as 63%, 71% and 75%, respectively. Addition of the optimal concentration of WV at mid log phase at 0.63% for TN114, and 1.25% for PP803 and the mixed culture significantly increased the ALA content by 3.7-4.2 times (128, 90 and 131 μM, respectively) compared to their controls. ALA production cost could be reduced approximately 31 times with WV on the basis of the amount of levulinic acid used. Effluent containing ALA for using in agriculture could be achieved by treating the RSW with the selected ALA producer R. palustris strains under the optimized condition with a little WV additive.

Blood interference in fiber-optical based fluorescence guided resection of glioma using 5-aminolevulinic acid

NASA Astrophysics Data System (ADS)

Haj-Hosseini, Neda; Lowndes, Shannely; Salerud, Göran; Wårdell, Karin

2011-03-01

Fluorescence guidance in brain tumor resection is performed intra-operatively where bleeding is included. When using fiber-optical probes, the transmission of light to and from the tissue is totally or partially blocked if a small amount of blood appears in front of the probe. Sometimes even after rinsing with saline, the remnant blood cells on the optical probe head, disturb the measurements. In such a case, the corresponding spectrum cannot be reliably quantified and is therefore discarded. The optimal case would be to calculate and take out the blood effect systematically from the collected signals. However, the first step is to study the pattern of blood interference in the fluorescence spectrum. In this study, a fiber-optical based fluorescence spectroscopy system with a laser excitation light of 405 nm (1.4 J/cm2) was used during fluorescence guided brain tumor resection using 5-aminolevulinic acid (5-ALA). The blood interference pattern in the fluorescence spectrum collected from the brain was studied in two patients. The operation situation was modeled in the laboratory by placing blood drops from the finger tip on the skin of forearm and the data was compared to the brain in vivo measurements. Additionally, a theoretical model was developed to simulate the blood interference pattern on the skin autofluorescence. The blood affects the collected fluorescence intensity and leaves traces of oxy and deoxy-hemoglobin absorption peaks. According to the developed theoretical model, the autofluorescence signal is considered to be totally blocked by an approximately 500 μm thick blood layer.

Initiation of Autophagy by Photodynamic Therapy

PubMed Central

Kessel, David; Oleinick, Nancy L.

2010-01-01

Photodynamic therapy (PDT) involves the irradiation of photosensitized cells with light. Depending on localization of the photosensitizing agent, the process can induce photodamage to the endoplasmic reticulum (ER), mitochondria, plasma membrane, and/or lysosomes. When ER or mitochondria are targeted, antiapoptotic proteins of the Bcl-2 family are especially sensitive to photodamage. Both apoptosis and autophagy can occur after PDT, autophagy being associated with enhanced survival at low levels of photodamage to some cells. Autophagy can become a cell-death pathway if apoptosis is inhibited or when cells attempt to recycle damaged constituents beyond their capacity for recovery. While techniques associated with characterization of autophagy are generally applicable, PDT introduces additional factors related to unknown sites of photodamage that may alter autophagic pathways. This chapter discusses issues that may arise in assessing autophagy after cellular photodamage. PMID:19216899

Hybrid systems based on gold nanostructures and porphyrins as promising photosensitizers for photodynamic therapy.

PubMed

Ferreira, Daniele C; Monteiro, Camila S; Chaves, Claudilene R; Sáfar, Gustavo A M; Moreira, Roberto L; Pinheiro, Maurício V B; Martins, Dayse C S; Ladeira, Luiz Orlando; Krambrock, Klaus

2017-02-01

Gold nanostructures of two different shapes (spheres and rods) were synthesized to form a colloidal hybrid system with 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin tosylate salt (H 2 TM4PyP(OTs) 4 ) (POR) for applications in photodynamic therapy (PDT) using light in the visible spectral range. Electron paramagnetic resonance (EPR) experiments in combination with spin trapping were used for the detection of reactive oxygen species (ROS) and evaluation of the efficiency of these novel hybrid systems as photosensitizers. It is shown that the hybrid system consisting of gold nanorods (AuNR) and porphyrin (POR) is by far more efficient than its isolated components. This enhanced efficiency is explained by a synergetic effect between the AuNR and the porphyrin, wherein a rapid energy transfer from the former to the latter produces a large amount of singlet oxygen followed by its conversion into hydroxyl radicals. The mechanism was investigated using different spin traps and different ROS inhibitors. On the other hand, spherical gold nanoparticles (AuNP) do not show this synergetic effect. The synergetic effect for gold nanorods/POR hybrid is attributed to a larger field enhancement close to the gold nanorod surface in addition to the electrostatic attraction between the components of the hybrid system. Copyright © 2016 Elsevier B.V. All rights reserved.

Overcoming photodynamic resistance and tumor targeting dual-therapy mediated by indocyanine green conjugated gold nanospheres.

PubMed

Li, Wei; Guo, Xiaomeng; Kong, Fenfen; Zhang, Hanbo; Luo, Lihua; Li, Qingpo; Zhu, Chunqi; Yang, Jie; Du, Yongzhong; You, Jian

2017-07-28

Photodynamic therapy (PDT) and photothermal therapy (PTT) have captured much attention due to the great potential to cure malignant tumor. Nevertheless, photodynamic resistance of cancer cells has limited the further efficacy of PDT. Unfortunately, the resistance mechanism and efforts to overcome the resistance still have been rarely reported so far. Here, we report a nanosystem with specific tumor targeting for combined PDT and PTT mediated by near-infrared (NIR) light, which was established by covalently conjugating indocyanine green (ICG) and TNYL peptide onto the surface of hollow gold nanospheres (HAuNS). Our nanosystem (TNYL-ICG-HAuNS) was proved to possess significantly increased light stability, reactive oxygen species (ROS) production and photothermal effect under NIR light irradiation, thus presenting a remarkably enhanced antitumor efficacy. The up-regulation of nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) in cancer cells during PDT induced a significant increase of ABCG2, NQO-1 and HIF-1α expression, causing PDT resistance of the cells. Interestingly, ABCG2 expression could almost keep a normal level in the whole PDT process mediated by TNYL-ICG-HAuNS. After repeated irradiations, TNYL-ICG-HAuNS could still produce almost constant ROS in cells while the Nrf2 expression reduced significantly. Furthermore, PDT resistance induced an obvious decrease of the internalization of free ICG, but didn't influence the cell uptake of TNYL-ICG-HAuNS. Our data explained that TNYL-ICG-HAuNS could overcome the photodynamic resistance of cancer cells, acting as a promising modality for simultaneous photothermal and photodynamic cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

A new NIR-triggered doxorubicin and photosensitizer indocyanine green co-delivery system for enhanced multidrug resistant cancer treatment through simultaneous chemo/photothermal/photodynamic therapy.

PubMed

Yu, Yanna; Zhang, Zhipeng; Wang, Yun; Zhu, Hao; Li, Fangzhou; Shen, Yuanyuan; Guo, Shengrong

2017-09-01

It is a great challenge to combat multidrug resistant (MDR) cancer effectively. To address this issue, we developed a new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase-change property of 1-tetradecanol at its melting point of 39°C, which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF-7/ADR cells. This nano-sized system was constructed by filling the interior of AuNCs with DOX, ICG and 1-tetradecanol, and modifying the surface with biotinylated poly (ethylene glycol) via Au-S bonds, termed as DOX/ICG@biotin-PEG-AuNC-PCM. The DOX and ICG co-release from DOX/ICG@biotin-PEG-AuNC-PCM was much faster in PBS at 40°C or under 808nm NIR irradiation at 2.5W/cm 2 than at 37°C (e.g. 67.27% or 80.31% vs. 5.57% of DOX, 76.08% vs. 3.83% of ICG for 20min). The flow cytometry and confocal laser scanning microscopy (CLSM) results showed, the AuNCs were taken up by MCF-7/ADR cells via endocytosis, thus enhancing DOX uptake; the biotin on AuNCs facilitated this endocytosis; NIR irradiation caused the heating of the AuNCs, triggering the DOX and ICG co-release and enhancing the distribution of DOX in nuclei, the released ICG generated ROS to take photodynamic therapy. Due to the above unique properties, DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumor effects under NIR irradiation, its IC 50 against MCF-7/ADR cells was very low, only 0.48µg/mL, much smaller than that of free DOX (74.51μg/mL). A new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase-change property of 1-tetradecanol at its melting point of 39°C, was prepared, termed as DOX

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

A Strategy Using Photodynamic Therapy and Clofibric Acid to Treat Peritoneal Dissemination of Ovarian Cancer.

PubMed

Yokoyama, Yoshihito; Shigeto, Tatsuhiko; Miura, Rie; Kobayashi, Asami; Mizunuma, Makito; Yamauchi, Aisa; Futagami, Masayuki; Mizunuma, Hideki

2016-01-01

The current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer. Nude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC. Rats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines. The results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.

Biochemical changes in cutaneous squamous cell carcinoma submitted to PDT using ATR-FTIR spectroscopy

NASA Astrophysics Data System (ADS)

Lima, Cassio A.; Goulart, Viviane P.; de Castro, Pedro A. A.; Correa, Luciana; Benetti, Carolina; Zezell, Denise M.

2015-06-01

Nonmelanoma skin cancers are the most common form of malignancy in humans. Between the traditional treatment ways, the photodynamic therapy (PDT) is a promising alternative which is minimally invasive and do not requires surgical intervention or exposure to ionizing radiation. The understanding of the cascade of effects playing role in PDT is not fully understood, so that define and understand the biochemical events caused by photodynamic effect will hopefully result in designing better PDT protocols. In this study we investigated the potential of the FTIR spectroscopy to assess the biochemical changes caused by photodynamic therapy after 10 and 20 days of treatment using 5-aminolevulinic acid (ALA) as precursor of the photosensitizer photoporphyrin IX (PpIX). The amplitude values of second derivative from vibrational modes obtained with FTIR spectroscopy showed similar behavior with the morphological features observed in histopathological analysis, which showed active lesions even 20 days after PDT. Thus, the technique has the potential to be used to complement the investigation of the main biochemical changes that photodynamic therapy promotes in tissue.

A laser-spectroscopy complex for fluorescent diagnostics and photodynamic therapy of age-related macula degeneration

NASA Astrophysics Data System (ADS)

Shevchik, S. A.; Meerovich, Gennadii A.; Budzinskaya, M. V.; Ermakova, N. A.; Kharnas, Sergey S.; Loschenov, Victor B.

2004-06-01

A laser-spectroscopy complex was developed for fluorescent diagnostics and photodynamic therapy of age related macula degeneration using the Russian photosensitizer Photosense. The complex is based on slit lamp which was additionally equipped with an optical adapter, and the video adapter allows to combine the procedure of photodynamic therapy and the control of its carrying in the frame work of one procedure. The sensitivity and spatial resolution of the complex were investigated using a special test object. The availability of the developed complex and Photosense itself was examined on experimental animals.

Effectiveness of repeated photodynamic therapy in the elimination of intracanal Enterococcus faecalis biofilm: an in vitro study.

PubMed

Prażmo, Ewa Joanna; Godlewska, Renata Alicja; Mielczarek, Agnieszka Beata

2017-04-01

The study aimed to investigate the effectiveness of photodynamic therapy in the elimination of intracanal Enterococcus faecalis biofilm and to analyse how a repeated light irradiation, replenishment of oxygen and photosensitiser affect the results of the photodynamic disinfecting protocol. After chemomechanical preparation, 46 single-rooted human teeth were infected with a clinical strain of E. faecalis and incubated for a week in microaerobic conditions. The experimental procedures included groups of single application of photodynamic therapy, two cycles of PDT, irrigation with 5.25% NaOCl solution and negative and positive control. The number of residing bacterial colonies in the root canals was determined based on the CFU/ml method. In the group of preparations irrigated with NaOCl, bacterial colonies were not observed. A single PDT eliminated 45% of the initial CFU/ml. Repeated PDT eradicated 95% of the intracanal bacterial biofilm. Photodynamic therapy has a high potential for the elimination of E. faecalis biofilm. There is a safe therapeutic window where photoinduced disinfection can be used as an adjuvant to conventional endodontic treatment, which remains the most effective.

Difunctional bacteriophage conjugated with photosensitizers for Candida albicans-targeting photodynamic inactivation.

PubMed

Dong, Shuai; Shi, Hongxi; Zhang, Xintong; Chen, Xi; Cao, Donghui; Mao, Chuanbin; Gao, Xiang; Wang, Li

2018-01-01

Candida albicans is the most prevalent fungal pathogen of the human microbiota, causing infections ranging from superficial infections of the skin to life-threatening systemic infections. Due to the increasing occurrence of antibiotic-resistant C. albicans strains, new approaches to control this pathogen are needed. Photodynamic inactivation is an emerging alternative to treat infections based on the interactions between visible light and photosensitisers, in which pheophorbide a (PPA) is a chlorophyll-based photosensitizer that could induce cell death after light irradiation. Due to PPA's phototoxicity and low efficiency, the main challenge is to implement photosensitizer cell targeting and attacking. In this study, PPA was conjugated with JM-phage by EDC/NHS crosslinking. UV-Vis spectra was used to determine the optimum conjugation percentages of PPA and JM-phage complex for photodynamic inactivation. After photodynamic inactivation, the efficacy of PPA-JM-phage was assessed by performing in vitro experiments, such as MTS assay, scanning electron microscopy, measurement of dysfunctional mitochondria, ROS accumulation, S cell arrest and apoptotic pathway. A single-chain variable-fragment phage (JM) with high affinity to MP65 was screened from human single-fold single-chain variable-fragment libraries and designed as a binding target for C. albicans cells. Subsequently, PPa was integrated into JM phage to generate a combined nanoscale material, which was called PPA-JM-phage. After photodynamic inactivation, the growth of C. albicans was inhibited by PPA-JM-phage and apoptosis was observed. Scanning electron microscopy analysis revealed shrinking and rupturing of C. albicans . We also found that depolarization of mitochondrial membrane potential was decreased and intracellular reactive oxygen species levels were elevated significantly in C. albicans inhibited by PPA-JM-phage. Additionally, PPA-JM-phage also lead to S-phase arrest, and metacaspase activation

Difunctional bacteriophage conjugated with photosensitizers for Candida albicans-targeting photodynamic inactivation

PubMed Central

Dong, Shuai; Shi, Hongxi; Zhang, Xintong; Chen, Xi; Cao, Donghui; Mao, Chuanbin; Gao, Xiang; Wang, Li

2018-01-01

Background Candida albicans is the most prevalent fungal pathogen of the human microbiota, causing infections ranging from superficial infections of the skin to life-threatening systemic infections. Due to the increasing occurrence of antibiotic-resistant C. albicans strains, new approaches to control this pathogen are needed. Photodynamic inactivation is an emerging alternative to treat infections based on the interactions between visible light and photosensitisers, in which pheophorbide a (PPA) is a chlorophyll-based photosensitizer that could induce cell death after light irradiation. Due to PPA’s phototoxicity and low efficiency, the main challenge is to implement photosensitizer cell targeting and attacking. Methods In this study, PPA was conjugated with JM-phage by EDC/NHS crosslinking. UV-Vis spectra was used to determine the optimum conjugation percentages of PPA and JM-phage complex for photodynamic inactivation. After photodynamic inactivation, the efficacy of PPA-JM-phage was assessed by performing in vitro experiments, such as MTS assay, scanning electron microscopy, measurement of dysfunctional mitochondria, ROS accumulation, S cell arrest and apoptotic pathway. Results A single-chain variable-fragment phage (JM) with high affinity to MP65 was screened from human single-fold single-chain variable-fragment libraries and designed as a binding target for C. albicans cells. Subsequently, PPa was integrated into JM phage to generate a combined nanoscale material, which was called PPA-JM-phage. After photodynamic inactivation, the growth of C. albicans was inhibited by PPA-JM-phage and apoptosis was observed. Scanning electron microscopy analysis revealed shrinking and rupturing of C. albicans. We also found that depolarization of mitochondrial membrane potential was decreased and intracellular reactive oxygen species levels were elevated significantly in C. albicans inhibited by PPA-JM-phage. Additionally, PPA-JM-phage also lead to S-phase arrest, and

Photodynamic inactivation assisted by localized surface plasmon resonance of silver nanoparticles: In vitro evaluation on Escherichia coli and Streptococcus mutans.

PubMed

Ribeiro, Martha S; de Melo, Luciana S A; Farooq, Sajid; Baptista, Alessandra; Kato, Ilka T; Núñez, Silvia C; de Araujo, Renato E

2018-06-01

Localized surface plasmon resonance (LSPR) of gold nanoparticles has been reported to increase the antimicrobial effect of the photodynamic therapy. Although silver nanoparticles (AgNPs) are an efficient growth inhibitor of microorganisms, no studies exploring LSPR of AgNPs to enhance the photodynamic inactivation (PDI) have been related. In this work, we described the LSPR phenomenon of AgNP sand investigated its interaction with riboflavin, a natural photosensitizer. We evaluated the use of AgNPs coated with pectin (p-AgNP) in riboflavin (Rb)-mediated PDI of Escherichia coli (Gram- bacteria) and Streptococcus mutans (Gram + bacteria) using a blue light-emitting diode (λ = 455 ± 20 nm) of optical power 200 mW. Irradiance was 90 mW/cm 2 and radiant exposure varied according to the time exposure. Uptake of Rb and p-AgNP by the cells was evaluated by measuring the supernatant absorption spectra of the samples. We observed that LSPR of p-AgNPs was able to enhance the riboflavin photodynamic action on S. mutans but not on E. coli, probably due to the lower uptake of Rb by E. coli. Taken together, our results provide insights to explore the use of the LPRS promoted by silver nanostructures to optimize antimicrobial PDI protocols. Copyright © 2018 Elsevier B.V. All rights reserved.

Photodynamic therapy toward selective endometrial ablation

NASA Astrophysics Data System (ADS)

Tadir, Yona; Tromberg, Bruce J.; Krasieva, Tatiana B.; Berns, Michael W.

1993-05-01

Potential applications of photodynamic therapy for endometrial disease are discussed. Experimental models that may lead to diagnosis and treatment of endometriosis as well as selective endometrial ablation are summarized.

New hybrid composites for photodynamic therapy: synthesis, characterization and biological study

NASA Astrophysics Data System (ADS)

Kutsevol, N.; Naumenko, A.; Harahuts, Yu.; Chumachenko, V.; Shton, I.; Shishko, E.; Lukianova, N.; Chekhun, V.

2018-04-01

Photodynamic therapy is a procedure that uses a photosensitizing drug to apply light therapy selectively to target cancer treatment. This study is focused on a synthesis and characterization of a new hybrid nanocomposites based on the branched copolymers dextran-polyacrylamide in nonionic, D-g-PAA and anionic D-g-PAA(PE) form, with incorporated gold nanoparticles (AuNPs) and photosensitizer chlorin e6 (Ce6) simultaneously. Double polymer/AuNPs and trial polymer/AuNPs/Ce6 were studied by TEM, UV-visible, SOSG fluorescence. It was found the drastic difference for absorbance for trial nanosystems synthesized in nonionic and anionic polymers matrices. It was established that for the nanocomposite synthesised in anionic polymer matrix with the Ce6:Au mass ratio 1:10 generation of singlet oxygen (1O2) was quite close to that for free Ce6. The study of ability of this nanosystem to sensitize MT-4 cells to photodynamic damage has shown that the nanocomposite, that contained AuNPs during the synthesis of which HAuCl4:NaBH4 mass ratio was 1:2 showed higher photodynamic activity, than Ce6 itself. Nanosystem D70-g-PAA(PE)/AuNPs/Ce6 can be recommended to experiment in vivo.

5-Aminolevulinic Acid Accumulation in a Cerebral Infarction Mimicking High-Grade Glioma.

PubMed

Behling, Felix; Hennersdorf, Florian; Bornemann, Antje; Tatagiba, Marcos; Skardelly, Marco

2016-08-01

5-Aminolevulinic acid (5-ALA) has become an integral part in the neurosurgical treatment of malignant glioma. Over time, several other tumor entities have been identified to metabolize 5-ALA and show a similar fluorescence pattern during surgical resection. This case report is the first description of 5-ALA accumulation in postischemic cerebral tissue. This evidence questions the assumption that 5-ALA accumulation in glioma is exclusively attributed to tumor infiltration. Instead, 5-ALA accumulation can also occur beyond the tumor borders and may be partially ascribed to inflammatory changes in the surrounding brain tissue. A 64-year old woman presented with episodes of apraxia and a ring-enhancing lesion in postcontrast T1-weighted magnetic resonance sequences suggestive of high grade glioma. Strong fluorescence was observed during 5-ALA-guided resection. However, although the frozen section was inconclusive, the final histopathologic examination revealed a stage II cerebral infarction. 5-ALA accumulation in postischemic cerebral tissue should be considered for intended supramarginal resections near eloquent brain regions. Therefore, sufficient preoperative imaging should regularly include magnetic resonance imaging spectroscopy and perfusion sequences to ascertain the proper diagnosis. Moreover, further research is warranted to determine the role of 5-ALA accumulation in postischemic and inflammatory brain tissue. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Antimicrobial Photodynamic Inactivation and Antitumor Photodynamic Therapy with Fullerenes

NASA Astrophysics Data System (ADS)

de Freitas, Lucas F.

2016-04-01

This book provides detailed and current information on using fullerenes (bucky-balls) in photodynamic therapy (PDT), one of the most actively studied applications of photonic science in healthcare. This will serve as a useful source for researchers working in photomedicine and nanomedicine, especially those who are investigating PDT for cancer treatment and infectious disease treatment. The book runs the gamut from an introduction to the history and chemistry of fullerenes and some basic photochemistry, to the application of fullerenes as photosensitizers for cancer and antimicrobial inactivation.

Intraparticle FRET for Enhanced Efficiency of Two-Photon Activated Photodynamic Therapy.

PubMed

Cao, Hongqian; Yang, Yang; Qi, Yanfei; Li, Yue; Sun, Bingbing; Li, Ying; Cui, Wei; Li, Juan; Li, Junbai

2018-06-01

Photodynamic therapy (PDT) still faces two main problems on cancer therapy. One is how to improve PDT efficiency against hypoxic environment of tumors. The other one is how to overcome the limit of short wavelength light to increase PDT treatment depth. In this work, an intraparticle fluorescence resonance energy transfer (FRET) platform is designed to address these problems together. The nanoparticles are doped with multicomponents, such as catalase, two-photon dyes, and traditional photosensitizers, with a simple "one-pot" and green method. On the one hand, catalase can catalyze intracellular H 2 O 2 into O 2 and promote PDT efficiency. One the other hand, photosensitizers can be excited indirectly by two-photon lasers through an intraparticle FRET mechanism, which results in deeper tissue penetration for PDT. These properties are verified through the material induced cytotoxicity in light or in dark and in vivo blocking blood-vessel experiment. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Photodynamic Therapy in Treatment of Oral Lichen Planus

PubMed Central

Mostafa, Diana; Tarakji, Bassel

2015-01-01

Oral lichen planus (OLP) is a relatively common chronic immunologic mucocutaneous disorder. Although there are many presenting treatments, some of them proved its failure. Recently, the use of photodynamic therapy (PDT) has been expanding due to its numerous advantages, as it is safe, convenient, and non-invasive and has toxic effect towards selective tissues. This article provides comprehensive review on OLP, its etiology, clinical features and recent non-pharmacological treatments. We also describe the topical PDT and its mechanisms. Our purpose was to evaluate the efficacy of PDT in treatment of OLP through collecting the data of the related clinical studies. We searched in PubMed website for the clinical studies that were reported from 2000 to 2014 using specific keywords: “photodynamic therapy” and “treatment of oral lichen planus”. Inclusion criteria were English publications only were concerned. In the selected studies of photodynamic treatment, adult patients (more than 20 years) were conducted and the OLP lesions were clinically and histologically confirmed. Exclusion criteria were classical and pharmacological treatments of OLP were excluded and also the using of PDT on skin lesions of lichen planus. We established five clinical studies in this review where all of them reported improvement and effectiveness of PDT in treatment of OLP lesions. The main outcome of comparing the related clinical studies is that the photodynamic is considered as a safe, effective and promising treatment modality for OLP. PMID:25883701

"Smart" nickel oxide based core-shell nanoparticles for combined chemo and photodynamic cancer therapy.

PubMed

Bano, Shazia; Nazir, Samina; Munir, Saeeda; AlAjmi, Mohamed Fahad; Afzal, Muhammad; Mazhar, Kehkashan

2016-01-01

We report "smart" nickel oxide nanoparticles (NOPs) as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA) connected bovine serum albumin (BSA) shell on entrapped doxorubicin (DOX). The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions) while a robust release was found under red light exposure (in 1/2 hour under λmax=655 nm, 50 mW/cm(2), at pH=5.5). The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy.

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

Novel applications of photoacoustic spectroscopy in life sciences

NASA Astrophysics Data System (ADS)

Stolik, S.

2004-10-01

The Photoacoustic Spectroscopy, based on the generation of acoustic waves following the absorption of the modulated light by an enclosed material, was discovered in 1880 by Alexander Graham Bell. There are a lot of remarkable achievements in this topic since those days. It has been intended to present a relatively new tool to the researchers in biological areas and, simultaneously, to propose new fields of investigation to those who have been attracted by physics. The application of Photoacoustic trace gas detection to the determination of ethylene content in mice exhalation is described as a biomarker of free radicals production. It has been demonstrated the feasibility of studying the lipid peroxidation in vivo by this technique. Specifically, the results of δ-aminolevulinic acid administration in mice are presented. This drug has been used to induce Protoporphyrin IX production and ultimately to apply the Photodynamic Therapy, a recent method in cancer treatment. A kinetic study of Protoporphyrin IX production in mice skin and blood after δ-aminolevulinic acid administration in different doses is also shown. This study was performed using Photoacoustic Spectroscopy in solids.

Anti-angiogenic treatment (Bevacizumab) improves the responsiveness of photodynamic therapy in colorectal cancer.

PubMed

Peng, Cheng-Liang; Lin, Hua-Ching; Chiang, Wei-Lun; Shih, Ying-Hsia; Chiang, Ping-Fang; Luo, Tsai-Yueh; Cheng, Chun-Chia; Shieh, Ming-Jium

2018-06-09

Photodynamic therapy (PDT) is a new treatment utilizing the combined action of photosensitizers and light for the treatment of various cancers. The mechanisms for tumor destruction after PDT include direct tumor cell kill by singlet oxygen species (OS), indirect cell kill via vascular damage, and an elicited immune response. However, it has been reported that many cellular activators, including vascular endothelial growth factor (VEGF), are produced by tumor cells after PDT. In this study, we demonstrate that meta-tetra(hydroxyphenyl) chlorin (mTHPC)-based photodynamic therapy combined with bevacizumab (Avastin™), an anti-VEGF neutralizing monoclonal antibody that blocks the binding of VEGF to its receptor, can enhance the effectiveness of each treatment modality. We evaluated the efficacy of bevacizumab-based anti-angiogenesis in combination with PDT as well as the resulting VEGF levels in a mouse model of human colon cancer. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to assess VEGF concentrations in the various treatment groups, and confocal imaging and high performance liquid chromatography (HPLC) analyses were used to measure the distribution and concentration of mTHPC in tumors. Our results demonstrate that combination of PDT followed by bevacizumab significantly elicits a greater tumor response whereas bevacizumab treatment prior to PDT led to a reduced tumor response. Immunostaining and ELISA analyses revealed a lower expression of VEGF in tumors treated with combination therapy of PDT followed by bevacizumab. However, bevacizumab treatment decreased the accumulation of mTHPC in tumors 24 h after administration, which complemented the results of decreased anti-tumor efficacy of bevacizumab followed by PDT. Copyright © 2018. Published by Elsevier B.V.

Nontumor photodynamic therapy

NASA Astrophysics Data System (ADS)

van den Bergh, Hubert

1997-12-01

Photodynamic therapy (PDT) has become an approved treatment for different types of cancer in many countries over the last few years. As an example one might mention PDT of the early stages of bronchial or esophageal cancer which have been treated with only about 20% recurrence being observed over several years of follow-up. The low degree of invasion of PDT, as compared to most alternative treatments as well as minimal sided effects, and good repeatability, all speak for this treatment modality. Improved and cheap screening procedures, that are now being developed for the early stage disease, will lead to a more frequent application of PDT for these indications. Detailed studies of PDT showed that certain dyes, after systematic or topical application, could be taken up more in neoplastic tissue as compared to the surrounding normal tissue in the clinical context, thus leading to 'selective' or at least partially selective destruction of the tumor following light application. This selectivity of uptake of certain compounds in hyperproliferative tissue, as well as the observation that PDT can lead to blood vessel stasis, suggested that photodynamic therapy might be worth trying in non-tumor disease. Some of the diseases associated with hyperproliferation and/or neovascularization which are being considered for PDT are listed in table I.

Fractional Ablative Laser Followed by Transdermal Acoustic Pressure Wave Device to Enhance the Drug Delivery of Aminolevulinic Acid: In Vivo Fluorescence Microscopy Study.

PubMed

Waibel, Jill S; Rudnick, Ashley; Nousari, Carlos; Bhanusali, Dhaval G

2016-01-01

Topical drug delivery is the foundation of all dermatological therapy. Laser-assisted drug delivery (LAD) using fractional ablative laser is an evolving modality that may allow for a greater precise depth of penetration by existing topical medications, as well as more efficient transcutaneous delivery of large drug molecules. Additional studies need to be performed using energy-driven methods that may enhance drug delivery in a synergistic manner. Processes such as iontophoresis, electroporation, sonophoresis, and the use of photomechanical waves aid in penetration. This study evaluated in vivo if there is increased efficacy of fractional CO2 ablative laser with immediate acoustic pressure wave device. Five patients were treated and biopsied at 4 treatment sites: 1) topically applied aminolevulinic acid (ALA) alone; 2) fractional ablative CO2 laser and topical ALA alone; 3) fractional ablative CO2 laser and transdermal acoustic pressure wave device delivery system; and 4) topical ALA with transdermal delivery system. The comparison of the difference in the magnitude of diffusion with both lateral spread of ALA and depth diffusion of ALA was measured by fluorescence microscopy. For fractional ablative CO2 laser, ALA, and transdermal acoustic pressure wave device, the protoporphyrin IX lateral fluorescence was 0.024 mm on average vs 0.0084 mm for fractional ablative CO2 laser and ALA alone. The diffusion for the acoustic pressure wave device was an order of magnitude greater. We found that our combined approach of fractional ablative CO2 laser paired with the transdermal acoustic pressure wave device increased the depth of penetration of ALA.

Photodynamic inactivation of antigenic determinants of single-stranded DNA bacteriophage phiX174

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khan, N.C.; Poddar, R.K.

1974-05-01

Bacteriophage phi X174 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 phi X174 coat proteins are partly responsible for the loss of plaque-forming ability, whereas the ''spikes'' aremore » either poor antigens or insensitive to photodynamic treatment. (auth)« less

Novel drug delivery strategies for porphyrins and porphyrin precursors

NASA Astrophysics Data System (ADS)

Morrow, D. I. J.; Donnelly, R. F.

2009-06-01

superficial lesions, such as actinic keratosis. In addition, photodynamic antimicrobial chemotherapy (PACT) is attracting increasing interest for the treatment of infection. However, delivery strategies for topical PDT and PACT are still based on application of rather simplistic cream and solution formulations, with little consideration given to thermodynamics, targeting or the physicochemical properties of the active agent. Purpose-designed dosage forms for topical delivery of aminolevulinic acid or its esters include creams containing penetration enhancers and/or iron chelators, pressure sensitive patches and bioadhesive patches. Such systems aim to enhance drug delivery across the stratum corneum and keratinised debris overlying neoplastic lesions and improve subsequent protoporphyrin IX (PpIX) production. The alternative to using porphyrin precursors is the use of pre-formed photosensitisers. However, owing to their relatively high molecular weights, conventional topical application is not appropriate. Innovative strategies, such as the use of needle-free injections and microneedle arrays, bypass the stratum corneum, enabling rapid and targeted delivery not only porphyrin precursors but also pre-formed photosensitisers. This presentation will review drug delivery work published to date in the fields of PDT and PACT. In addition, the benefits of employing the latest advances in pharmaceutical technology will be highlighted.

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.

Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.

PubMed

Chang, Ming-Hsiang; Pai, Chin-Ling; Chen, Ying-Chen; Yu, Hsiu-Ping; Hsu, Chia-Yen; Lai, Ping-Shan

2018-02-22

Nanocarrier-based delivery systems are promising strategies for enhanced therapeutic efficacy and safety of toxic drugs. Photodynamic therapy (PDT)-a light-triggered chemical reaction that generates localized tissue damage for disease treatments-usually has side effects, and thus patients receiving photosensitizers should be kept away from direct light to avoid skin phototoxicity. In this study, a clinically therapeutic antibody cetuximab (C225) was conjugated to the surface of methoxy poly(ethylene glycol)- b -poly(lactide) (mPEG- b -PLA) micelles via thiol-maleimide coupling to allow tumor-targetable chlorin e6 (Ce6) delivery. Our results demonstrate that more C225-conjugated Ce6-loaded polymeric micelles (C225-Ce6/PM) were selectively taken up than Ce6/PM or IgG conjugated Ce6/PM by epidermal growth factor receptor (EGFR)-overexpressing A431 cells observed by confocal laser scanning microscopy (CLSM), thereby decreasing the IC 50 value of Ce6-mediated PDT from 0.42 to 0.173 μM. No significant differences were observed in cellular uptake study or IC 50 value between C225-Ce6/PM and Ce6/PM groups in lower EGFR expression HT-29 cells. For antitumor study, the tumor volumes in the C225-Ce6/PM-PDT group (percentage of tumor growth inhibition, TGI% = 84.8) were significantly smaller than those in the Ce6-PDT (TGI% = 38.4) and Ce6/PM-PDT groups (TGI% = 53.3) ( p < 0.05) at day 21 through reduced cell proliferation in A431 xenografted mice. These results indicated that active EGFR targeting of photosensitizer-loaded micelles provides a possible way to resolve the dose-limiting toxicity of conventional photosensitizers and represents a potential delivery system for PDT in a clinical setting.

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.

Doxorubicin-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers for NIR-triggered photodynamic therapy and enhanced chemotherapy in drug-resistant breast cancers.

PubMed

Zeng, Leyong; Pan, Yuanwei; Tian, Ying; Wang, Xin; Ren, Wenzhi; Wang, Shouju; Lu, Guangming; Wu, Aiguo

2015-07-01

The combination therapy has exhibited important potential for the treatment of cancers, especially for drug-resistant cancers. In this report, bi-functional nanoprobes based on doxorubicin (DOX)-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers (FA-NPs-DOX) were synthesized for in vivo near infrared (NIR)-triggered inorganic photodynamic therapy (PDT) and enhanced chemotherapy to overcome the multidrug resistance (MDR) in breast cancers. Using the up-conversion luminescence (UCL) performance of NaYF4:Yb/Tm converting near-infrared (NIR) into ultraviolent (UV) lights, reactive oxygen species (ROS) were triggered from TiO2 inorganic photosensitizers for PDT under the irradiation of a 980 nm laser, by which the deep-penetration and low photo-damage could be reached. Moreover, nanocarrier delivery and folic acid (FA) targeting promoted the cellular uptake, and accelerated the release of DOX in drug-sensitive MCF-7 and resistant MCF-7/ADR cells. The toxicity assessment in vitro and in vivo revealed the good biocompatibility of the as-prepared FA-NPs-DOX nanocomposites. By the combination of enhanced chemotherapy and NIR-triggered inorganic PDT, the viability of MCF-7/ADR cells could decrease by 53.5%, and the inhibition rate of MCF-7/ADR tumors could increase up to 90.33%, compared with free DOX. Therefore, the MDR of breast cancers could be obviously overcome by enhanced chemotherapy and NIR-triggered inorganic PDT of FA-NPs-DOX nanocomposites under the excitation of a 980 nm laser. Copyright © 2015 Elsevier Ltd. All rights reserved.

Surface charge-conversion polymeric nanoparticles for photodynamic treatment of urinary tract bacterial infections

NASA Astrophysics Data System (ADS)

Liu, Shijie; Qiao, Shenglin; Li, Lili; Qi, Guobin; Lin, Yaoxin; Qiao, Zengying; Wang, Hao; Shao, Chen

2015-12-01

Urinary tract infections are typical bacterial infections which result in a number of economic burdens. With increasing antibiotic resistance, it is urgent that new approaches are explored that can eliminate pathogenic bacteria without inducing drug resistance. Antimicrobial photodynamic therapy (PDT) is a new promising tactic. It is a gentle in situ photochemical reaction in which a photosensitizer (PS) generates reactive oxygen species (ROS) under laser irradiation. In this work, we have demonstrated Chlorin e6 (Ce6) encapsulated charge-conversion polymeric nanoparticles (NPs) for efficiently targeting and killing pathogenic bacteria in a weakly acidic urinary tract infection environment. Owing to the surface charge conversion of NPs in an acidic environment, the NPs exhibited enhanced recognition for Gram-positive (ex. S. aureus) and Gram-negative (ex. E. coli) bacteria due to the charge interaction. Also, those NPs showed significant antibacterial efficacy in vitro with low cytotoxicity. The MIC value of NPs to E. coli is 17.91 μg ml-1, compared with the free Ce6 value of 29.85 μg ml-1. Finally, a mouse acute cystitis model was used to assess the photodynamic therapy effects in urinary tract infections. A significant decline (P < 0.05) in bacterial cells between NPs and free Ce6 occurred in urine after photodynamic therapy treatment. And the plated counting results revealed a remarkable bacterial cells drop (P < 0.05) in the sacrificed bladder tissue. Above all, this nanotechnology strategy opens a new door for the treatment of urinary tract infections with minimal side effects.

Surface charge-conversion polymeric nanoparticles for photodynamic treatment of urinary tract bacterial infections.

PubMed

Liu, Shijie; Qiao, Shenglin; Li, Lili; Qi, Guobin; Lin, Yaoxin; Qiao, Zengying; Wang, Hao; Shao, Chen

2015-12-11

Urinary tract infections are typical bacterial infections which result in a number of economic burdens. With increasing antibiotic resistance, it is urgent that new approaches are explored that can eliminate pathogenic bacteria without inducing drug resistance. Antimicrobial photodynamic therapy (PDT) is a new promising tactic. It is a gentle in situ photochemical reaction in which a photosensitizer (PS) generates reactive oxygen species (ROS) under laser irradiation. In this work, we have demonstrated Chlorin e6 (Ce6) encapsulated charge-conversion polymeric nanoparticles (NPs) for efficiently targeting and killing pathogenic bacteria in a weakly acidic urinary tract infection environment. Owing to the surface charge conversion of NPs in an acidic environment, the NPs exhibited enhanced recognition for Gram-positive (ex. S. aureus) and Gram-negative (ex. E. coli) bacteria due to the charge interaction. Also, those NPs showed significant antibacterial efficacy in vitro with low cytotoxicity. The MIC value of NPs to E. coli is 17.91 μg ml(-1), compared with the free Ce6 value of 29.85 μg ml(-1). Finally, a mouse acute cystitis model was used to assess the photodynamic therapy effects in urinary tract infections. A significant decline (P < 0.05) in bacterial cells between NPs and free Ce6 occurred in urine after photodynamic therapy treatment. And the plated counting results revealed a remarkable bacterial cells drop (P < 0.05) in the sacrificed bladder tissue. Above all, this nanotechnology strategy opens a new door for the treatment of urinary tract infections with minimal side effects.

Modulation of δ-Aminolevulinic Acid Dehydratase Activity by the Sorbitol-Induced Osmotic Stress in Maize Leaf Segments.

PubMed

Jain, M; Tiwary, S; Gadre, R

2018-01-01

Osmotic stress induced with 1 M sorbitol inhibited δ-aminolevulinic acid dehydratase (ALAD) and aminolevulinic acid (ALA) synthesizing activities in etiolated maize leaf segments during greening; the ALAD activity was inhibited to a greater extent than the ALA synthesis. When the leaves were exposed to light, the ALAD activity increased for the first 8 h, followed by a decrease observed at 16 and 24 h in both sorbitol-treated and untreated leaf tissues. The maximum inhibition of the enzyme activity was observed in the leaf segments incubated with sorbitol for 4 to 8 h. Glutamate increased the ALAD activity in the in vitro enzymatic preparations obtained from the sorbitol-treated leaf segments; sorbitol inhibited the ALAD activity in the preparations from both sorbitol-treated and untreated leaves. It was suggested that sorbitol-induced osmotic stress inhibits the enzyme activity by affecting the ALAD induction during greening and regulating the ALAD steady-state level of ALAD in leaf cells. The protective effect of glutamate on ALAD in the preparations from the sorbitol-treated leaves might be due to its stimulatory effect on the enzyme.

Molecular imaging of photodynamic therapy

NASA Astrophysics Data System (ADS)

Chang, Sung K.; Errabelli, Divya; Rizvi, Imran; Solban, Nicolas; O'Riordan, Katherine; Hasan, Tayyaba

2006-02-01

Recent advances in light sources, detectors and other optical imaging technologies coupled with the development of novel optical contrast agents have enabled real-time, high resolution, in vivo monitoring of molecular targets. Noninvasive monitoring of molecular targets is particularly relevant to photodynamic therapy (PDT), including the delivery of photosensitizer in the treatment site and monitoring of molecular and physiological changes following treatment. Our lab has developed optical imaging technologies to investigate these various aspects of photodynamic therapy (PDT). We used a laser scanning confocal microscope to monitor the pharmacokinetics of various photosensitizers in in vitro as well as ex vivo samples, and developed an intravital fluorescence microscope to monitor photosensitizer delivery in vivo in small animals. A molecular specific contrast agent that targets the vascular endothelial growth factor (VEGF) was developed to monitor the changes in the protein expression following PDT. We were then able to study the physiological changes due to post-treatment VEGF upregulation by quantifying vascular permeability with in vivo imaging.

Intracellular Targeting Specificity of Novel Phthalocyanines Assessed in a Host-Parasite Model for Developing Potential Photodynamic Medicine

PubMed Central

Dutta, Sujoy; Ongarora, Benson G.; Li, Hairong; Vicente, Maria da Graca H.; Kolli, Bala K.; Chang, Kwang Poo

2011-01-01

Photodynamic therapy, unlikely to elicit drug-resistance, deserves attention as a strategy to counter this outstanding problem common to the chemotherapy of all diseases. Previously, we have broadened the applicability of this modality to photodynamic vaccination by exploiting the unusual properties of the trypanosomatid protozoa, Leishmania, i.e., their innate ability of homing to the phagolysosomes of the antigen-presenting cells and their selective photolysis therein, using transgenic mutants endogenously inducible for porphyrin accumulation. Here, we extended the utility of this host-parasite model for in vitro photodynamic therapy and vaccination by exploring exogenously supplied photosensitizers. Seventeen novel phthalocyanines (Pcs) were screened in vitro for their photolytic activity against cultured Leishmania. Pcs rendered cationic and soluble (csPcs) for cellular uptake were phototoxic to both parasite and host cells, i.e., macrophages and dendritic cells. The csPcs that targeted to mitochondria were more photolytic than those restricted to the endocytic compartments. Treatment of infected cells with endocytic csPcs resulted in their accumulation in Leishmania-containing phagolysosomes, indicative of reaching their target for photodynamic therapy, although their parasite versus host specificity is limited to a narrow range of csPc concentrations. In contrast, Leishmania pre-loaded with csPc were selectively photolyzed intracellularly, leaving host cells viable. Pre-illumination of such csPc-loaded Leishmania did not hinder their infectivity, but ensured their intracellular lysis. Ovalbumin (OVA) so delivered by photo-inactivated OVA transfectants to mouse macrophages and dendritic cells were co-presented with MHC Class I molecules by these antigen presenting cells to activate OVA epitope-specific CD8+T cells. The in vitro evidence presented here demonstrates for the first time not only the potential of endocytic csPcs for effective photodynamic therapy

Efficacy of iontophoresis-assisted ablative fractional laser photodynamic therapy with short incubation time for the treatment of actinic keratosis: 12-month follow-up results of a prospective, randomised, comparative trial.

PubMed

Choi, Seung-Hwan; Kim, Tae-Hoon; Song, Ki-Hoon

2017-06-01

Iontophoresis is a transdermal drug-delivery technique that enhances the transport of ionic species across membranes and may have significant benefit for the treatment of actinic keratosis (AK) by ablative fractional laser-primed photodynamic therapy (AFL-PDT). The aims of this study were to compare the efficacy, recurrence rate, cosmetic outcome and safety of iontophoresis-assisted AFL-PDT with 2h of incubation vs. those of conventional AFL-PDT with 2- and 3-h incubation in patients with facial and scalp AK. Patients were randomly assigned to iontophoresis-assisted AFL-PDT with a 2-h incubation time (group A) and conventional AFL-PDT with a 2-h (group B) and 3-h (group C) incubation time. All patients underwent AFL-PDT, and group A patients were assigned to treatment with iontophoresis after methyl-aminolevulinate (MAL) application. After 2 or 3h, MAL-applied lesions were irradiated using a red light. Patients were followed up at 1-week, 3 months and 12 months after treatment. Efficacy, cosmetic outcomes and adverse events were assessed. In total, 41 patients (160 AK lesions) completed the study and were evaluated. Efficacy was significantly higher in Group A (88.7%) than in Group B (73.2%); the efficacy of groups A and C (92.2%) at 3 months follow-up was comparable. The recurrence rates were not significantly different between the groups at 12 months (P=0.841). The three groups did not differ in terms of cosmetic outcomes and safety. Iontophoresis-assisted AFL-PDT showed higher efficacy than AFL-PDT with short incubation time. Iontophoresis may effectively reduce the incubation time in AFL-PDT. Copyright © 2017 Elsevier B.V. All rights reserved.

Urea enhances the photodynamic efficiency of methylene blue.

PubMed

Nuñez, Silvia C; Yoshimura, Tania M; Ribeiro, Martha S; Junqueira, Helena C; Maciel, Cleiton; Coutinho-Neto, Maurício D; Baptista, Maurício S

2015-09-01

Methylene blue (MB) is a well-known photosensitizer used mostly for antimicrobial photodynamic therapy (APDT). MB tends to aggregate, interfering negatively with its singlet oxygen generation, because MB aggregates lean towards electron transfer reactions, instead of energy transfer with oxygen. In order to avoid MB aggregation we tested the effect of urea, which destabilizes solute-solute interactions. The antimicrobial efficiency of MB (30 μM) either in water or in 2M aqueous urea solution was tested against a fungus (Candida albicans). Samples were kept in the dark and irradiation was performed with a light emitting diode (λ = 645 nm). Without urea, 9 min of irradiation was needed to achieve complete microbial eradication. In urea solution, complete eradication was obtained with 6 min illumination (light energy of 14.4 J). The higher efficiency of MB/urea solution was correlated with a smaller concentration of dimers, even in the presence of the microorganisms. Monomer to dimer concentration ratios were extracted from the absorption spectra of MB solutions measured as a function of MB concentration at different temperatures and at different concentrations of sodium chloride and urea. Dimerization equilibrium decreased by 3 and 6 times in 1 and 2M urea, respectively, and increased by a factor of 6 in 1M sodium chloride. The destabilization of aggregates by urea seems to be applied to other photosensitizers, since urea also destabilized aggregation of Meso-tetra(4-n-methyl-pyridyl)porphyrin, which is a positively charged porphyrin. We showed that urea destabilizes MB aggregates mainly by causing a decrease in the enthalpic gain of dimerization, which was exactly the opposite of the effect of sodium chloride. In order to understand this phenomenon at the molecular level, we computed the free energy for the dimer association process (ΔG(dimer)) in aqueous solution as well as its enthalpic component in aqueous and in aqueous/urea solutions by molecular dynamics

Photodynamic Therapy with Hypericin Improved by Targeting HSP90 Associated Proteins

PubMed Central

Solár, Peter; Chytilová, Mária; Solárová, Zuzana; Mojžiš, Ján; Ferenc, Peter; Fedoročko, Peter

2011-01-01

In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic activity, viability and cell number when combined with photodynamic therapy with hypericin. Moreover, IC10 concentation of 17-DMAG resulted in significant increase of SKBR-3 cells in G1 phase of the cell cycle, followed by an increase of cells in G2 phase when combined with photodynamic therapy. Furthermore, 17-DMAG already decreased HER2, Akt, P-Erk1/2 and survivin protein levels in SKBR-3 cells a short time after its application. In this regard, 17-DMAG protected also SKBR-3 cells against both P-Erk1/2 as well as survivin upregulations induced by photodynamic therapy with hypericin. Interestingly, IC10 concentration of 17-DMAG led to total depletion of Akt, P-Erk1/2 proteins and to decrease of survivin level at 48 h. On the other hand, 17-DMAG did not change HER2 relative expression in SKBR-3 cells, but caused a significant decrease of HER2 mRNA in MCF-7 cells characterized by low HER2 expression. These results show that targeting HSP90 client proteins increases the efficiency of antineoplastic effect of photodynamic therapy in vitro. PMID:27721334

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.

Smart Photosensitizer: Tumor-Triggered Oncotherapy by Self-Assembly Photodynamic Nanodots.

PubMed

Jia, Yuhua; Li, Jinyu; Chen, Jincan; Hu, Ping; Jiang, Longguang; Chen, Xueyuan; Huang, Mingdong; Chen, Zhuo; Xu, Peng

2018-05-09

Clinical photosensitizers suffer from the disadvantages of fast photobleaching and high systemic toxicities because of the off-target photodynamic effects. To address these problems, we report a self-assembled pentalysine-phthalocyanine assembly nanodots (PPAN) fabricated by an amphipathic photosensitizer-peptide conjugate. We triggered the photodynamic therapy effects of photosensitizers by precisely controlling the assembly and disintegration of the nanodots. In physiological aqueous conditions, PPAN exhibited a size-tunable spherical conformation with a highly positive shell of the polypeptides and a hydrophobic core of the π-stacking Pc moieties. The assembly conformation suppressed the fluorescence and the reactive oxygen species generation of the monomeric photosensitizer molecules (mono-Pc) and thus declined the photobleaching and off-target photodynamic effects. However, tumor cells disintegrated PPAN and released the mono-Pc molecules, which exhibited fluorescence for detection and the photodynamic effects for the elimination of the tumor tissues. The molecular dynamics simulations revealed the various assembly configurations of PPAN and illustrated the assembly mechanism. At the cellular level, PPAN exhibited a remarkable phototoxicity to breast cancer cells with the IC 50 values in a low nanomolar range. By using the subcutaneous and orthotopic breast cancer animal models, we also demonstrated the excellent antitumor efficacies of PPAN in vivo.

Application of 1,2-diethyl-3-hydroxypyridin-4-one to enhance tissue selectivity for photodynamic therapy of the bladder

NASA Astrophysics Data System (ADS)

Chang, Shi-Chung; MacRobert, Alexander J.; Porter, John B.; Bown, Stephen G.

1995-03-01

Five-aminolaevulinic acid (ALA) induced protoporphyrin IX (PpIX) has proven to be a useful photosensitizer for photodynamic therapy (PDT). In living cells, the conversion of PpIX to photoinactive haem is catalyzed by ferrochelatase in the presence of tissue iron and inhibition of this final committed step results in increased accumulation of PpIX. The in vivo effect of a new iron chelator, 1,2-diethyl-3-hydroxypyridin-4-one (CP94), on the buildup of PpIX in different bladder layers was evaluated. In CP94 treated rats, 5 - 7 hours after intravesical instillation of ALA solution, the fluorescence intensity of PpIX in the urothelium was doubled whilst in the muscle layer it remained low at a similar level to those seen without the iron chelator. With CP94, further reduction of skin photosensitization is possible as a similar photodynamic effect on the bladder could be achieved at lower ALA concentration. The addition of CP94 seems an effective and convenient way to potentiate ALA induced PpIX tissue selectivity.

Monoglycoconjugated phthalocyanines: effect of sugar and linkage on photodynamic activity.

PubMed

Lafont, Dominique; Zorlu, Yunus; Savoie, Huguette; Albrieux, Florian; Ahsen, Vefa; Boyle, Ross W; Dumoulin, Fabienne

2013-09-01

Click chemistry can be advantageously used to graft carbohydrates on phthalocyanines which are potent photosensitisers, but the effect of the presence of triazole moieties on photodynamic efficiency was not investigated systematically to date. The nature and linkage of the sugar were investigated in order to define structure-activity relationships. Two sets of monoglycoconjugated water-soluble phthalocyanines have been designed and their photodynamic activity and uptake investigated in HT-29 human colon adenocarcinoma cells. Carbohydrates: galactose, mannose or lactose were grafted onto Zn(II) phthalocyanines either by glycosylation or by click reaction. The triazole linkage formed by click conjugation lowered the biological efficiency for mannose and galactose, compared to classical glycosylation grafting. The mannose conjugate formed by glycosylation was the most photodynamically active, without correlation with the photosensitiser cell uptake. Copyright © 2012 Elsevier B.V. All rights reserved.

Synthesis of acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, Luc

2003-06-24

A process of preparing an acid addition salt of delta-aminolevulinc acid comprising: a) dissolving a lower alkyl 5-bromolevulinate and hexamethylenetetramine in a solvent selected from the group consisting of water, ethyl acetate, chloroform, acetone, ethanol, tetrahydrofuran and acetonitrile, to form a quaternary ammonium salt of the lower alkyl 5-bromolevulinate; and b) hydrolyzing the quaternary ammonium salt with an inorganic acid to form an acid addition salt of delta-aminolevulinic acid.

Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy Against Human Cervical Cancer Cells In Vitro and in Mice

PubMed Central

Gadzinski, Jill A.; Guo, Jianxia; Philips, Brian J.; Basse, Per; Craig, Ethan K.; Bailey, Lisa; Comerci, John T.; Eiseman, Julie L.

2017-01-01

Background Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distrubtion were determined. For in vitro Pc 4 photodynamic therapy cells were irradiated at 667nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight h after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. Results The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6μM and 0.016μM and >10μM and 0.026μM; as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26μM and 0.01μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program. PMID:28890844

Photodynamic Therapy for Gynecological Diseases and Breast Cancer

PubMed Central

Shishkova, Natashis; Kuznetsova, Olga; Berezov, Temirbolat

2012-01-01

Photodynamic therapy (PDT) is a minimally invasive and promising new method in cancer treatment. Cytotoxic reactive oxygen species (ROS) are generated by the tissue-localized non-toxic sensitizer upon illumination and in the presence of oxygen. Thus, selective destruction of a targeted tumor may be achieved. Compared with traditional cancer treatment, PDI has advantages including higher selectivity and lower rate of toxicity. The high degree of selectivity of the proposed method was applied to cancer diagnosis using fluorescence. This article reviews previous studies done on PDT treatment and photodetection of cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, ovarian and breast cancer, and PDT application in treating non-cancer lesions. The article also highlights the clinical responses to PDT, and discusses the possibility of enhancing treatment efficacy by combination with immunotherapy and targeted therapy. PMID:23691448

Improved Photodynamic Efficacy of Zn(II) Phthalocyanines via Glycerol Substitution

PubMed Central

Chin, Yunni; Lim, Siang Hui; Zorlu, Yunus; Ahsen, Vefa; Kiew, Lik Voon; Chung, Lip Yong; Dumoulin, Fabienne; Lee, Hong Boon

2014-01-01

Phthalocyanines are excellent photosensitizers for photodynamic therapy as they have strong absorbance in the near infra-red region which is most relevant for in vivo activation in deeper tissular regions. However, most phthalocyanines present two major challenges, ie, a strong tendency to aggregate and low water-solubility, limiting their effective usage clinically. In the present study, we evaluated the potential enhancement capability of glycerol substitution on the photodynamic properties of zinc (II) phthalocyanines (ZnPc). Three glycerol substituted ZnPc, 1–3, (tetra peripherally, tetra non-peripherally and mono iodinated tri non-peripherally respectively) were evaluated in terms of their spectroscopic properties, rate of singlet oxygen generation, partition coefficient (log P), intracellular uptake, photo-induced cytotoxicity and vascular occlusion efficiency. Tetrasulfonated ZnPc (ZnPcS4) was included as a reference compound. Here, we showed that 1–3 exhibited 10–100 nm red-shifted absorption peaks with higher molar absorptivity, and at least two-fold greater singlet oxygen generation rates compared to ZnPcS4. Meanwhile, phthalocyanines 1 and 2 showed more hydrophilic log P values than 3 consistent with the number of glycerol attachments but 3 was most readily taken up by cells compared to the rest. Both phthalocyanines 2 and 3 exhibited potent phototoxicity against MCF-7, HCT-116 and HSC-2 cancer cell-lines with IC50 ranging 2.8–3.2 µM and 0.04–0.06 µM respectively, while 1 and ZnPcS4 (up to 100 µM) failed to yield determinable IC50 values. In terms of vascular occlusion efficiency, phthalocyanine 3 showed better effects than 2 by causing total occlusion of vessels with diameter <70 µm of the chorioallantoic membrane. Meanwhile, no detectable vascular occlusion was observed for ZnPcS4 with treatment under similar experimental conditions. These findings provide evidence that glycerol substitution, in particular in structures 2 and 3, is able

Improved photodynamic efficacy of Zn(II) phthalocyanines via glycerol substitution.

PubMed

Chin, Yunni; Lim, Siang Hui; Zorlu, Yunus; Ahsen, Vefa; Kiew, Lik Voon; Chung, Lip Yong; Dumoulin, Fabienne; Lee, Hong Boon

2014-01-01

Phthalocyanines are excellent photosensitizers for photodynamic therapy as they have strong absorbance in the near infra-red region which is most relevant for in vivo activation in deeper tissular regions. However, most phthalocyanines present two major challenges, ie, a strong tendency to aggregate and low water-solubility, limiting their effective usage clinically. In the present study, we evaluated the potential enhancement capability of glycerol substitution on the photodynamic properties of zinc (II) phthalocyanines (ZnPc). Three glycerol substituted ZnPc, 1-3, (tetra peripherally, tetra non-peripherally and mono iodinated tri non-peripherally respectively) were evaluated in terms of their spectroscopic properties, rate of singlet oxygen generation, partition coefficient (log P), intracellular uptake, photo-induced cytotoxicity and vascular occlusion efficiency. Tetrasulfonated ZnPc (ZnPcS4) was included as a reference compound. Here, we showed that 1-3 exhibited 10-100 nm red-shifted absorption peaks with higher molar absorptivity, and at least two-fold greater singlet oxygen generation rates compared to ZnPcS4. Meanwhile, phthalocyanines 1 and 2 showed more hydrophilic log P values than 3 consistent with the number of glycerol attachments but 3 was most readily taken up by cells compared to the rest. Both phthalocyanines 2 and 3 exhibited potent phototoxicity against MCF-7, HCT-116 and HSC-2 cancer cell-lines with IC50 ranging 2.8-3.2 µM and 0.04-0.06 µM respectively, while 1 and ZnPcS4 (up to 100 µM) failed to yield determinable IC50 values. In terms of vascular occlusion efficiency, phthalocyanine 3 showed better effects than 2 by causing total occlusion of vessels with diameter <70 µm of the chorioallantoic membrane. Meanwhile, no detectable vascular occlusion was observed for ZnPcS4 with treatment under similar experimental conditions. These findings provide evidence that glycerol substitution, in particular in structures 2 and 3, is able to improve

Photodynamic effect of radiation with the wavelength 405 nm on the cells of microorganisms sensitised by metalloporphyrin compounds

NASA Astrophysics Data System (ADS)

Korchenova, M. V.; Tuchina, E. S.; Shvayko, V. Y.; Gulkhandanyan, A. G.; Zakoyan, A. A.; Kazaryan, R. K.; Gulkhandanyan, G. V.; Dzhagarov, B. M.; Tuchin, V. V.

2016-06-01

We have studied the photodynamic activity of photosensitisers based on metalloporphyrins. New metalloporphyrin compounds are synthesised and characterised, the quantum yields of the singlet oxygen formation are analysed. It is shown that when the photodynamic effect is implemented using the metalloporphyrins with Zn ions and butyl radical in the 3rd and 4th positions of the pyridine ring, the number of opportunistic bacteria, such as Staphylococcus aureus (antibiotic-sensitives and antibiotic-resistant strains), Staphylococcus simulans and Escherichia coli is efficiently reduced by 90% - 99%.

Delta-aminolevulinate dehydratase activity and oxidative stress markers in preeclampsia.

PubMed

de Lucca, Leidiane; Rodrigues, Fabiane; Jantsch, Letícia B; Kober, Helena; Neme, Walter S; Gallarreta, Francisco M P; Gonçalves, Thissiane L

2016-12-01

Preeclampsia is an important pregnancy-specific multisystem disorder characterized by the onset of hypertension and proteinuria. It is of unknown etiology and involves serious risks for the pregnant women and fetus. One of the main factors involved in the pathophysiology of preeclampsia is oxidative stress, where excess free radicals produce harmful effects, including damage to macromolecules such as lipids, proteins and DNA. In addition, the sulfhydryl delta-aminolevulinate dehydratase enzyme (δ-ALA-D) that is part of the heme biosynthetic pathway in pro-oxidant conditions can be inhibited, which may result in the accumulation of 5-aminolevulinic acid (ALA), associated with the overproduction of free radicals, suggesting it to be an indirect marker of oxidative stress. As hypertensive pregnancy complications are a major cause of morbidity and mortality maternal and fetal where oxidative stress appears to be an important factor involved in preeclampsia, the aim of this study was to evaluate the activity of δ-ALA-D and classic oxidative stress markers in the blood of pregnant women with mild and severe preeclampsia. The analysis and quantification of the following oxidative stress markers were performed: thiobarbituric acid-reactive species (TBARS); presence of protein and non-protein thiol group; quantification of vitamin C; Catalase and δ-ALA--D activities in samples of blood of pregnant women with mild preeclampsia (n=25), with severe preeclampsia (n=30) and in a control group of healthy pregnant women (n=30). TBARS was significantly higher in women with preeclampsia, while the presence of thiol groups, levels of vitamin C, catalase and δ-ALA-D activity were significantly lower in groups of pregnant women with preeclampsia compared with healthy women. In addition, the results showed no significant difference between groups of pregnant women with mild and severe preeclampsia. The data suggest a state of increased oxidative stress in pregnant women with

Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract--a pilot study.

PubMed

Kacerovská, Denisa; Pizinger, Karel; Majer, Filip; Smíd, Frantisek

2008-01-01

Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.

Photodynamic therapy in the treatment of epithelial potentially malignant disorders of the mouth: advantages and disadvantages

NASA Astrophysics Data System (ADS)

Gaimari, G.; Russo, C.; Palaia, G.; Tenore, G.; Del Vecchio, A.; Romeo, U.

2016-03-01

Introduction: Leukoplakia is a potentially malignant epithelial lesion with carcinomatous percentages transformation comprehended between 1% and 7% for the homogeneous forms and from 4% to 15% for the non-homogeneous ones. Their removal can be performed by scalpel or laser surgery (excision or vaporization). Photodynamic therapy (PDT) is a bloodless treatment option, based on the involvement of three elements: light, photosensitizer and oxygen. When the molecules of the photosensitizer are activated by a low power laser, energy is transferred to molecular oxygen creating highly reactive radicals of oxygen, that have a cytotoxic effect on target cells. Aim of the study: According to several studies in Literature, it has been decided to evaluate through an initial clinical trial, the efficacy of PDT using topical aminolevulinic acid (5-ALA) activated by a laser diode (λ = 635 nm) to treat potentially oral malignant lesions and to illustrate the advantages and disadvantages derived from the use of this technique. Materials and Methods: Five patients, affected by oral leukoplakia (OL) and oral verrucous leukoplakia (OVL) on the mucosal cheeks, labial commissure, fornix and retromolar areas, have been treated using the PDT. Irradiation time with Diode laser: 1000s. Irradiation mode: Scanning. 5 cycles of 3 minute + final cycle of 100 seconds. Each cycle has been interrupted by pauses of 3 minutes. Results and conclusion: PDT results to be effective in the treatment of OL, especially on OVL. In fact, OVL, due to its irregularity, has got an area of increased retention for the gel that is more difficult to be removed by salivary flow. This could explain the better results obtained in this case rather than in those ones of OL. Furthermore, the advantages have been represented by: less invasivity, high sensitivity for altered tissues, minimal scar tissue, less side effects and no pain during and after operation. In contrast to this, the disadvantages were: longer treatment

Hypericin-loaded lipid nanocapsules for photodynamic cancer therapy in vitro

NASA Astrophysics Data System (ADS)

Barras, Alexandre; Boussekey, Luc; Courtade, Emmanuel; Boukherroub, Rabah

2013-10-01

Hypericin (Hy), a naturally occurring photosensitizer (PS), is extracted from Hypericum perforatum plants, commonly known as St. John's wort. The discovery of the in vitro and in vivo photodynamic activities of hypericin as a photosensitizer generated great interest, mainly to induce a very potent antitumoral effect. However, this compound belongs to the family of naphthodianthrones which are known to be poorly soluble in physiological solutions and produce non-fluorescent aggregates (A. Wirz et al., Pharmazie, 2002, 57, 543; A. Kubin et al., Pharmazie, 2008, 63, 263). These phenomena can reduce its efficiency as a photosensitizer for the clinical application. In the present contribution, we have prepared, characterized, and studied the photochemical properties of Hy-loaded lipid nanocapsule (LNC) formulations. The amount of singlet oxygen (1O2) generated was measured by the use of p-nitroso-dimethylaniline (RNO) as a selective scavenger under visible light irradiation. Our results showed that Hy-loaded LNCs suppressed aggregation of Hy in aqueous media, increased its apparent solubility, and enhanced the production of singlet oxygen in comparison with free drug. Indeed, encapsulation of Hy in LNCs led to an increase of 1O2 quantum yield to 0.29-0.44, as compared to 0.02 reported for free Hy in water. Additionally, we studied the photodynamic activity of Hy-loaded LNCs on human cervical carcinoma (HeLa) and Human Embryonic Kidney (HEK) cells. The cell viability decreased radically to 10-20% at 1 μM, reflecting Hy-loaded LNC25 phototoxicity.Hypericin (Hy), a naturally occurring photosensitizer (PS), is extracted from Hypericum perforatum plants, commonly known as St. John's wort. The discovery of the in vitro and in vivo photodynamic activities of hypericin as a photosensitizer generated great interest, mainly to induce a very potent antitumoral effect. However, this compound belongs to the family of naphthodianthrones which are known to be poorly soluble in

The Role of Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia

PubMed Central

Tosti, Giulio; Iacobone, Anna Daniela; Preti, Eleonora Petra; Vaccari, Sabina; Barisani, Alessia; Pennacchioli, Elisabetta

2018-01-01

Background: vulvar intraepithelial neoplasia is a non-invasive precursor lesion found in 50–70% of patients affected by vulvar squamous cell carcinoma. In the past, radical surgery was the standard treatment for vulvar intraepithelial neoplasia, however, considering the psychological and physical morbidities related to extensive surgery, several less aggressive treatment modalities have been proposed since the late 1970s. Photodynamic therapy is an effective and safe treatment for cutaneous non-melanoma skin cancer, with favorable cosmetic outcomes. Methods: in the present paper, the results of selected studies on photodynamic therapy in the treatment of vulvar intraepithelial neoplasia are reported and discussed. Results: Overall, complete histological response rates ranged between 20% and 67% and symptom response rates ranged between 52% and 89% according to different studies and case series. Conclusions: the real benefit of photodynamic therapy in the setting of vulvar intraepithelial neoplasia lies in its ability to treat multi-focal disease with minimal tissue destruction, preservation of vulvar anatomy and excellent cosmetic outcomes. These properties explain why photodynamic therapy is an attractive option for vulvar intraepithelial neoplasia treatment. PMID:29393881

Fractional Resurfacing Aiding Photodynamic Therapy of a Recalcitrant Plantar Verruca

PubMed Central

Pope, Amy

2008-01-01

Fractional resurfacing has become a very popular laser modality in recent years, and photodynamic therapy (PDT) has become a mainstay of many practices treating a wide array of clinical entities. In this case report, we describe a recalcitrant verrucous lesion on the foot that is unresponsive to cryotherapy, pulsed dye laser, and pulsed dye laser with PDT. The lesion did, however, respond very well to the use of a fractional laser to enhance the penetration of the PDT photosensitizer and then responded to pulsed dye laser with PDT. Fractional resurfacing prior to PDT may be a novel dermatologic treatment approach, making PDT an even better treatment option in the future. PMID:21103307

The Antimicrobial Photodynamic Therapy in the Treatment of Peri-Implantitis

PubMed Central

Libotte, Fabrizio; Sabatini, Silvia; Grassi, Felice Roberto

2016-01-01

Introduction. The aim of this study is to demonstrate the effectiveness of addition of the antimicrobial photodynamic therapy to the conventional approach in the treatment of peri-implantitis. Materials and Methods. Forty patients were randomly assigned to test or control groups. Patients were assessed at baseline and at six (T1), twelve (T2), and twenty-four (T3) weeks recording plaque index (PlI), probing pocket depth (PPD), and bleeding on probing (BOP); control group received conventional periodontal therapy, while test group received photodynamic therapy in addition to it. Result. Test group showed a 70% reduction in the plaque index values and a 60% reduction in PD values compared to the baseline. BOP and suppuration were not detectable. Control group showed a significative reduction in plaque index and PD. Discussion. Laser therapy has some advantages in comparison to traditional therapy, with faster and greater healing of the wound. Conclusion. Test group showed after 24 weeks a better value in terms of PPD, BOP, and PlI, with an average pocket depth value of 2 mm, if compared with control group (3 mm). Our results suggest that antimicrobial photodynamic therapy with diode laser and phenothiazine chloride represents a reliable adjunctive treatment to conventional therapy. Photodynamic therapy should, however, be considered a coadjuvant in the treatment of peri-implantitis associated with mechanical (scaling) and surgical (grafts) treatments. PMID:27429618

Indole-3-acetic acid: a potential new photosensitizer for photodynamic therapy of acne vulgaris.

PubMed

Na, Jung-Im; Kim, So-Young; Kim, Jeong-Hye; Youn, Sang-Woong; Huh, Chang-Hun; Park, Kyoung-Chan

2011-03-01

ALA (5-aminolevulinic acid) photodynamic therapy (PDT) is a new treatment option for acne. However, it needs a relatively long incubation period and adverse effects are common. Indole-3-acetic acid (IAA) is not toxic by itself but produces free radicals with ultraviolet B. In this study we examined the potential of IAA as a photosensitizer for acne treatment. Free radical formation was measured after visible light irradiation of IAA. Antimicrobial effect was evaluated by assessing growth suppression of Propionibacterium acnes and Staphylococcus aureus after IAA PDT. To evaluate the histological changes, skin biopsies were performed on nude mice skin after IAA PDT. To evaluate the clinical efficacy of IAA PDT, 14 acne patients were treated with the following IAA PDT regimen: three times each with a 15 minutes incubation period and a 2-week interval. The number of inflammatory lesions and the amount of sebum secretion were then assessed. IAA produced free radicals with green light irradiation. Importantly, IAA lost its photosensitizing ability after exposure to certain amount of light. This implies IAA PDT would not require post-procedure photo-protection. The growth of P. acnes and S. aureus were significantly suppressed with IAA PDT. In addition, IAA PDT treated skin showed destruction of follicular ostia epithelium. Interestingly, there was no significant difference between a 4 hours and a 30 minutes incubation, which means that longer absorption time is not necessary for IAA PDT. In the clinical study, inflammatory lesions and sebum secretion were significantly reduced. The procedure was painless and no adverse effect was observed. Photo-protection was not performed and there were no further phototoxic responses. IAA PDT has therapeutic effects on acne via its antimicrobial activities, its sebum-reducing effect and through relieving follicular occlusion. It is a very simple and safe treatment option for acne. Copyright © 2011 Wiley-Liss, Inc.

Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

PubMed Central

Kaščáková, Slávka; Hofland, Leo J.; De Bruijn, Henriette S.; Ye, Yunpeng; Achilefu, Samuel; van der Wansem, Katy; van der Ploeg-van den Heuvel, Angelique; van Koetsveld, Peter M.; Brugts, Michael P.; van der Lelij, Aart-Jan; Sterenborg, Henricus J. C. M.; ten Hagen, Timo L. M.; Robinson, Dominic J.; van Hagen, Martin P.

2014-01-01

Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2 + AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate. PMID:25111655

Fluorescence Behavior and Dural Infiltration of Meningioma Analyzed by 5-Aminolevulinic Acid-Based Fluorescence: Operating Microscope Versus Mini-Spectrometer.

PubMed

Knipps, Johannes; Beseoglu, Kerim; Kamp, Marcel; Fischer, Igor; Felsberg, Joerg; Neumann, Lisa M; Steiger, Hans-Jakob; Cornelius, Jan F

2017-12-01

To compare fluorescence intensity of tumor specimens, as measured by a fluorescence-guided surgery microscope and a spectrometer, to evaluate tumor infiltration of dura mater around meningiomas with help of these 2 different 5-aminolevulinic acid (5-ALA)-based fluorescence tools, and to correlate fluorescence intensity with histopathologic data. In a clinical series, meningiomas were resected by 5-ALA fluorescence-guided surgery. Fluorescence intensity was semiquantitatively rated by the surgeon at predefined points. Biopsies were harvested and fluorescence intensity measured by a spectrometer and histopathologically analyzed. Sampling was realized at the level of the dura in a centrifugal direction. A total of 104 biopsies (n = 13 tumors) were analyzed. Specificity and sensitivity of the microscope were 0.96 and 0.53 and of the spectrometer 0.95 and 0.93, respectively. Fluorescence intensity as measured by the spectrometer was correlated to histologically confirmed tumor burden. In a centrifugal direction, tumor burden and fluorescence intensity continuously decreased (along the dural tail). Below a threshold value of 639 arbitrary units no tumor was histologically detectable. At the level of the dura the spectrometer was highly sensitive for detection of meningioma cells. The surgical microscope showed false negative results and missed residual tumor cells in more than one half of the cases. The complementary use of both fluorescence tools may improve resection quality. Copyright © 2017 Elsevier Inc. All rights reserved.

Photoelectron Transfer at ZnTPyP Self-Assembly/TiO2 Interfaces for Enhanced Two-Photon Photodynamic Therapy.

PubMed

Liu, Yanyan; Meng, Xianfu; Wang, Han; Tang, Zhongmin; Zuo, Changjing; He, Mingyuan; Bu, Wenbo

2018-01-17

Two-photon (TP) absorption nanomaterials are highly desirable for deep-tissue clinical diagnostics and orthotopic disease treatment. Here, a well-designed core/shell nanostructure was successfully synthesized with a ZnTPyP self-assembly nanocrystal (ZSN) inner core coated by a homogeneous TiO 2 layer outside (ZSN-TO). The ZSN is a good photosemiconductor, showing both one-photon (OP) and TP absorption properties for red fluorescence emission and electron-hole pair generation; TiO 2 with good biocompatibility acts as the electron acceptor, which can transfer photoelectron from ZSN to TiO 2 for highly effective electron-hole separation, favoring the production of long-life superoxide anion (O 2 •- ) by electrons and oxygen and strong oxidizing hydroxyl radical (•OH) by holes and surrounding H 2 O. Once pretreated with ZSN-TO, the simultaneous OP-405 nm or TP-800 nm laser stimulation and fluorescent imaging of reactive oxygen species (ROS) showed dynamical and continuous generation of ROS in HeLa cells, with cytotoxicity significantly increasing via the type-1-like photodynamic therapy process. The results demonstrated that the combination of organic ZSN with inorganic TiO 2 has great applications as an excellent photosensitizer for deep-tissue fluorescent imaging and noninvasive disease treatment via TP photodynamic therapy.

A robotic multi-channel platform for interstitial photodynamic therapy

PubMed Central

Sharikova, Anna V.; Finlay, Jarod C.; Dimofte, Andreea; Zhu, Timothy C.

2015-01-01

A custom-made robotic multichannel platform for interstitial photodynamic therapy (PDT) and diffuse optical tomography (DOT) was developed and tested in a phantom experiment. The system, which was compatible with the operating room (OR) environment, had 16 channels for independent positioning of light sources and/or isotropic detectors in separate catheters. Each channel’s motor had an optical encoder for position feedback, with resolution of 1.5 mm, and a maximum speed of 5 cm/s. Automatic calibration of detector positions was implemented using an optical diode beam that defined the starting position of each motor, and by means of feedback algorithms controlling individual channels. As a result, the accuracy of zero position of 0.1 mm for all channels was achieved. We have also employed scanning procedures where detectors automatically covered the appropriate range around source positions. Thus, total scan time for a typical optical properties (OP) measurement throughout the phantom was about 1.5 minutes with point sources. The OP were determined based on the measured light fluence rates. These enhancements allow a tremendous improvement of treatment quality for a bulk tumor compared to the systems employed in previous clinical trials. PMID:25914794

Phyto-management of chromium contaminated soils through sunflower under exogenously applied 5-aminolevulinic acid.

PubMed

Farid, Mujahid; Ali, Shafaqat; Rizwan, Muhammad; Ali, Qasim; Saeed, Rashid; Nasir, Tauqir; Abbasi, Ghulam Hasan; Rehmani, Muhammad Ishaq Asif; Ata-Ul-Karim, Syed Tahir; Bukhari, Syed Asad Hussain; Ahmad, Tanvir

2018-04-30

Soil contamination with heavy metals is threatening the food security around the globe. Chromium (Cr) contamination results in poor quality and reduction in yield of crops. The present research was performed to figure out the Cr toxicity in sunflower and the ameliorative role of 5-aminolevulinic acid (ALA) as a plant growth regulator. The sunflower (FH-614) was grown under increasing concentration of Cr (0, 5, 10 and 20mgkg -1 ) alone and/or in combination with 5-ALA (0, 10 and 20mgL -1 ). Results showed that Cr suppressed the overall growth, biomass, gas exchange attributes and chlorophyll content of sunflower plants. Moreover, lower levels of Cr (5 and 10mgkg -1 ) increased the production of reactive oxygen species (ROS) and electrolyte leakage (EL) along with the activities of antioxidant enzymes i.e., superoxide dismutase (SOD), guaiacole peroxidase (POD), ascorbate (APX), catalase (CAT). But at higher concentration of Cr (20mgkg -1 ), the activities of these enzymes presented a declining trend. However, the addition of 5-ALA significantly alleviated the Cr-induced toxicity in sunflower plant and enhanced the plant growth and biomass parameters along with increased chlorophyll content, gas exchange attributes, soluble proteins and soil plant analysis development (SPAD) values by scavenging the ROS and lowering down the EL. The 5-ALA also enhanced the activities of antioxidant enzymes at all levels of Cr. The increase in Cr concentration in all plant parts such as leaf, root and stem was directly proportional to the Cr concentration in soil. The application of 5-ALA further enhanced the uptake of Cr and its concentration in the plants. To understand this variation in response of plants to 5-ALA, detailed studies are required on plant biochemistry and genetic modifications. Copyright © 2018 Elsevier Inc. All rights reserved.

Optimal gadolinium dose level for magnetic resonance imaging (MRI) contrast enhancement of U87-derived tumors in athymic nude rats for the assessment of photodynamic therapy

NASA Astrophysics Data System (ADS)

Cross, Nathan; Varghai, Davood; Flask, Chris A.; Feyes, Denise K.; Oleinick, Nancy L.; Dean, David

2009-02-01

This study aims to determine the effect of varying gadopentetate dimeglumine (Gd-DTPA) dose on Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) tracking of brain tumor photodynamic therapy (PDT) outcome. Methods: We injected 2.5 x 105 U87 cells (derived from human malignant glioma) into the brains of six athymic nude rats. After 9, 12, and 13 days DCE-MRI images were acquired on a 9.4 T micro-MRI scanner before and after administration of 100, 150, or 200 μL of Gd-DTPA. Results: Tumor region normalized DCE-MRI scan enhancement at peak was: 1.217 over baseline (0.018 Standard Error [SE]) at the 100 μL dose, 1.339 (0.013 SE) at the 150 μL dose, and 1.287 (0.014 SE) at the 200 μL dose. DCE-MRI peak tumor enhancement at the 150 μL dose was significantly greater than both the 100 μL dose (p < 3.323E-08) and 200 μL dose (p < 0.0007396). Discussion: In this preliminary study, the 150 μL Gd-DTPA dose provided the greatest T1 weighted contrast enhancement, while minimizing negative T2* effects, in DCE-MRI scans of U87-derived tumors. Maximizing Gd-DTPA enhancement in DCE-MRI scans may assist development of a clinically robust (i.e., unambiguous) technique for PDT outcome assessment.

Deconvoluting heme biosynthesis to target blood-stage malaria parasites

PubMed Central

Sigala, Paul A; Crowley, Jan R; Henderson, Jeffrey P; Goldberg, Daniel E

2015-01-01

Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. DOI: http://dx.doi.org/10.7554/eLife.09143.001 PMID:26173178

5-ALA photopreparation using pulsed NIR enhances skin fluorescence via temperature-independent cell signaling pathways

NASA Astrophysics Data System (ADS)

Barolet, Augustin C.; Cormack, Gregory; Barolet, Daniel

2018-02-01

The effect of near infrared light (940 nm) on the conversion of 5-aminolevulinic acid (5-ALA) to PpIX, a compound involved in photodynamic therapy (PDT), was examined. The back skin of three test subjects was irradiated with continuous wavelength and pulsed infrared light at 940 nm. These irradiations took place 50-53, 24-29, and 8-14 hours prior to the application of the 5-ALA. After a three-hour incubation period with 5-ALA, a FluoDerm™device was used to measure the fluorescence of the skin (emitting wavelength: 400-420 nm; measuring excitation wavelength: 610-720 nm), a direct indication of the activity of 5-ALA. 5-ALA must penetrate the skin and then be converted to PpIX before any fluorescence increase can be observed. Results: For two patients (one was disqualified), the continuous wavelength, 50 hour pre-irradiation condition, the FluoDerm readings showed a 19 to 23% increase in fluorescence (p = 0.05) compared to the no-irradiation, 5-ALA only control.

Photodynamic therapy (PDT) utilizing PhotofrinR for treatment of early esophageal cancer

NASA Astrophysics Data System (ADS)

Overholt, Bergein F.; Panjehpour, Masoud; Teffeteller, Elmeria; Rose, S. Mark

1993-06-01

Four lesions of early carcinoma of the esophagus found during endoscopic biopsies in three patients were treated with photodynamic therapy. Follow-up biopsies over 9 - 24 months remain negative for carcinoma. Endoscopic ultrasonography is essential for proper staging and treatment planning for these patients. Photodynamic therapy may provide an alternative to surgical resection for early esophageal carcinoma or severe dysplasia in Barrett's esophagus.

Polymeric Nanoparticle-Based Photodynamic Therapy for Chronic Periodontitis in Vivo.

PubMed

de Freitas, Laura Marise; Calixto, Giovana Maria Fioramonti; Chorilli, Marlus; Giusti, Juçaíra Stella M; Bagnato, Vanderlei Salvador; Soukos, Nikolaos S; Amiji, Mansoor M; Fontana, Carla Raquel

2016-05-20

Antimicrobial photodynamic therapy (aPDT) is increasingly being explored for treatment of periodontitis. Here, we investigated the effect of aPDT on human dental plaque bacteria in suspensions and biofilms in vitro using methylene blue (MB)-loaded poly(lactic-co-glycolic) (PLGA) nanoparticles (MB-NP) and red light at 660 nm. The effect of MB-NP-based aPDT was also evaluated in a clinical pilot study with 10 adult human subjects with chronic periodontitis. Dental plaque samples from human subjects were exposed to aPDT-in planktonic and biofilm phases-with MB or MB-NP (25 µg/mL) at 20 J/cm² in vitro. Patients were treated either with ultrasonic scaling and scaling and root planing (US + SRP) or ultrasonic scaling + SRP + aPDT with MB-NP (25 µg/mL and 20 J/cm²) in a split-mouth design. In biofilms, MB-NP eliminated approximately 25% more bacteria than free MB. The clinical study demonstrated the safety of aPDT. Both groups showed similar improvements of clinical parameters one month following treatments. However, at three months ultrasonic SRP + aPDT showed a greater effect (28.82%) on gingival bleeding index (GBI) compared to ultrasonic SRP. The utilization of PLGA nanoparticles encapsulated with MB may be a promising adjunct in antimicrobial periodontal treatment.

Enhancing the photodynamic effect of hypericin in tumour spheroids by fractionated light delivery in combination with hyperoxygenation.

PubMed

Huygens, Ann; Kamuhabwa, Appolinary R; Van Laethem, An; Roskams, Tania; Van Cleynenbreugel, Ben; Van Poppel, Hendrik; Agostinis, Patrizia; De Witte, Peter A M

2005-06-01

The aim of this study was to explore the hypothesis of oxygen depletion during light irradiation as a possible explanation for the incomplete response seen after hypericin-mediated photodynamic therapy (PDT) under specific conditions. To investigate this, we performed PDT experiments using transitional cell carcinoma spheroids with fractionated light irradiation and hyperoxygenation. After 2-h incubation with 3 different hypericin concentrations, spheroids were irradiated either continuously or with fractionated light delivery. The effect of hyperoxygenation was investigated by bubbling normobaric oxygen in the solution surrounding the spheroids before continuous irradiation or during the dark interval of light fractionation. The PDT efficacy was evaluated with an MTT antiproliferation assay and apoptotic cells were visualized after PDT by DAPI staining. Our results show that fractionated light delivery with dark intervals ranging from 1 to 10 min does not enhance the PDT efficacy in spheroids at all, whereas hyperoxygenation, using appropriate hypericin concentrations and oxygenation intervals, results in a virtually complete malignant cell killing through apoptosis. This study suggests that oxygen depletion is the major source of relative treatment failure in hypericin-mediated PDT with spheroids, which can only be overcome with hyperoxygenation. Therefore, whole bladder wall PDT with hypericin is likely to become a very efficient antitumoural treatment against superficial bladder cancer, on the condition that instillation fluids are hyperoxygenated during light irradiation.

Possibility for a full optical determination of photodynamic therapy outcome

NASA Astrophysics Data System (ADS)

Vollet-Filho, J. D.; Menezes, P. F. C.; Moriyama, L. T.; Grecco, C.; Sibata, C.; Allison, R. R.; Castro e Silva, O.; Bagnato, V. S.

2009-05-01

The efficacy of photodynamic therapy (PDT) depends on a variety of parameters: concentration of the photosensitizer at the time of treatment, light wavelength, fluence, fluence rate, availability of oxygen within the illuminated volume, and light distribution in the tissue. Dosimetry in PDT requires the congregation of adequate amounts of light, drug, and tissue oxygen. The adequate dosimetry should be able to predict the extension of the tissue damage. Photosensitizer photobleaching rate depends on the availability of molecular oxygen in the tissue. Based on photosensitizers photobleaching models, high photobleaching has to be associated with high production of singlet oxygen and therefore with higher photodynamic action, resulting in a greater depth of necrosis. The purpose of this work is to show a possible correlation between depth of necrosis and the in vivo photosensitizer (in this case, Photogem®) photodegradation during PDT. Such correlation allows possibilities for the development of a real time evaluation of the photodynamic action during PDT application. Experiments were performed in a range of fluence (0-450 J/cm2) at a constant fluence rate of 250 mW/cm2 and applying different illumination times (0-1800 s) to achieve the desired fluence. A quantity was defined (ψ) as the product of fluorescence ratio (related to the photosensitizer degradation at the surface) and the observed depth of necrosis. The correlation between depth of necrosis and surface fluorescence signal is expressed in ψ and could allow, in principle, a noninvasive monitoring of PDT effects during treatment. High degree of correlation is observed and a simple mathematical model to justify the results is presented.

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

Site-specific antibody-liposome conjugation through copper-free click chemistry: a molecular biology approach for targeted photodynamic therapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Obaid, Girgis; Wang, Yucheng; Kuriakose, Jerrin; Broekgaarden, Mans; Alkhateeb, Ahmed; Bulin, Anne-Laure; Hui, James; Tsourkas, Andrew; Hasan, Tayyaba

2016-03-01

Nanocarriers, such as liposomes, have the ability to potentiate photodynamic therapy (PDT) treatment regimens by the encapsulation of high payloads of photosensitizers and enhance their passive delivery to tumors through the enhanced permeability and retention effect. By conjugating targeting moieties to the surface of the liposomal nanoconstructs, cellular selectivity is imparted on them and PDT-based therapies can be performed with significantly higher dose tolerances, as off-target toxicity is simultaneously reduced.1 However, the maximal benefits of conventional targeted nanocarriers, including liposomes, are hindered by practical limitations including chemical instability, non-selective conjugation chemistry, poor control over ligand orientation, and loss of ligand functionality following conjugation, amongst others.2 We have developed a robust, physically and chemically stable liposomal nanoplatform containing benzoporphyrin derivative photosensitizer molecules within the phospholipid bilayer and an optimized surface density of strained cyclooctyne moieties for `click' conjugation to azido-functionalized antibodies.3 The clinical chimeric anti-EGFR antibody Cetuximab is site-specifically photocrosslinked to a recombinant bioengineered that recognizes the antibody's Fc region, containing a terminal azide.4 The copper-free click conjugation of the bioengineered Cetuximab derivative to the optimized photosensitizing liposome provides exceptional control over the antibody's optimal orientation for cellular antigen binding. Importantly, the reaction occurs rapidly under physiological conditions, bioorthogonally (selectively in the presence of other biomolecules) and without the need for toxic copper catalysis.3 Such state-of-the-art conjugation strategies push the boundaries of targeted photodynamic therapy beyond the limitations of traditional chemical coupling techniques to produce more robust and effective targeted therapeutics with applications beyond

Performance of a contact textile-based light diffuser for photodynamic therapy.

PubMed

Khan, Tania; Unternährer, Merthan; Buchholz, Julia; Kaser-Hotz, Barbara; Selm, Bärbel; Rothmaier, Markus; Walt, Heinrich

2006-03-01

Medical textiles offer a unique contact opportunity that could provide value-added comfort, reliability, and safety for light or laser-based applications. We investigated a luminous textile diffuser for use in photodynamic therapy. Textile diffusers are produced by an embroidery process. Plastic optical fibers are bent and sewn into textile to release light by macrobending. A reflective backing is incorporated to improve surface homogeneity, intensity, and safety. Clonogenic assay (MCF-7 cells) and trypan blue exclusion (NuTu19 cells) tests were performed in vitro using 0.1μg/ml m-THPC with three textile diffusers and a standard front lens diffuser. Heating effects were studied in solution and on human skin. PDT application in vivo was performed with the textile diffuser on equine sarcoids (three animals, 50mW/cm(2), 10-20J) and eight research animals. Lastly, computer simulations were performed to see how the textile diffuser might work on a curved object. At low fluency rate, there is a trend for the textile diffuser to have lower survival rates than the front lens diffuser for both cell lines. The textile diffuser was observed to retain more heat over a long period (>1min). All animals tolerated the treatments well and showed similar initial reactions. The simulations showed a likely focusing effect in a curved geometry. The initial feasibility and application using a textile-based optical diffuser has been demonstrated. Possibilities that provide additional practical advantages of the textile diffuser are discussed.

Nonadiabatic Photodynamics of a Retinal Model in Polar and Nonpolar Environment

PubMed Central

2013-01-01

The nonadiabatic photodynamics of the all-trans-2,4-pentadiene-iminium cation (protonated Schiff base 3, PSB3) and the all-trans-3-methyl-2,4-pentadiene-iminium cation (MePSB3) were investigated in the gas phase and in polar (aqueous) and nonpolar (n-hexane) solutions by means of surface hopping using a multireference configuration-interaction (MRCI) quantum mechanical/molecular mechanics (QM/MM) level. Spectra, lifetimes for radiationless deactivation to the ground state, and structural and electronic parameters are compared. A strong influence of the polar solvent on the location of the crossing seam, in particular in the bond length alternation (BLA) coordinate, is found. Additionally, inclusion of the polar solvent changes the orientation of the intersection cone from sloped in the gas phase to peaked, thus enhancing considerably its efficiency for deactivation of the molecular system to the ground state. These factors cause, especially for MePSB3, a substantial decrease in the lifetime of the excited state despite the steric inhibition by the solvent. PMID:23470211

Conjugate of biotin with silicon(IV) phthalocyanine for tumor-targeting photodynamic therapy.

PubMed

Li, Ke; Qiu, Ling; Liu, Qingzhu; Lv, Gaochao; Zhao, Xueyu; Wang, Shanshan; Lin, Jianguo

2017-09-01

In order to improve the efficacy of photodynamic therapy (PDT), biotin was axially conjugated with silicon(IV) phthalocyanine (SiPc) skeleton to develop a new tumor-targeting photosensitizer SiPc-biotin. The target compound SiPc-biotin showed much higher binding affinity toward BR-positive (biotin receptor overexpressed) HeLa human cervical carcinoma cells than its precursor SiPc-pip. However, when the biotin receptors of HeLa cells were blocked by free biotin, >50% uptake of SiPc-biotin was suppressed, demonstrating that SiPc-biotin could selectively accumulate in BR-positive cancer cells via the BR-mediated internalization. The confocal fluorescence images further confirmed the target binding ability of SiPc-biotin. As a consequence of specificity of SiPc-biotin toward BR-positive HeLa cells, the photodynamic effect was also largely dependent on the BR expression level of HeLa cells. The photodynamic activities of SiPc-biotin against HeLa cells were dramatically reduced when the biotin receptors were blocked by the free biotin (IC 50 : 0.18μM vs. 0.46μM). It is concluded that SiPc-biotin can selectively damage BR-positive cancer cells under irradiation. Furthermore, the dark toxicity of SiPc-biotin toward human normal liver cell lines LO2 was much lower than that of its precursor SiPc-pip. The targeting photodynamic activity and low dark toxicity suggest that SiPc-biotin is a promising photosensitizer for tumor-targeting photodynamic therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Biomedical applications of nano-titania in theranostics and photodynamic therapy.

PubMed

Rehman, F U; Zhao, C; Jiang, H; Wang, X

2016-01-01

Titanium dioxide (TiO2) is one of the most abundantly used nanomaterials for human life. It is used in sunscreen, photovoltaic devices, biomedical applications and as a food additive and environmental scavenger. Nano-TiO2 in biomedical applications is well documented. It is used in endoprosthetic implants and early theranostics of neoplastic and non-neoplastic maladies as a photodynamic therapeutic agent and as vehicles in nano-drug delivery systems. Herein, we focus on the recent advancements and applications of nano-TiO2 in bio-nanotechnology, nanomedicine and photodynamic therapy (PDT).

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.

Singlet oxygen production by combining erythrosine and halogen light for photodynamic inactivation of Streptococcus mutans.

PubMed

Fracalossi, Camila; Nagata, Juliana Yuri; Pellosi, Diogo Silva; Terada, Raquel Sano Suga; Hioka, Noboru; Baesso, Mauro Luciano; Sato, Francielle; Rosalen, Pedro Luiz; Caetano, Wilker; Fujimaki, Mitsue

2016-09-01

Photodynamic inactivation of microorganisms is based on a photosensitizing substance which, in the presence of light and molecular oxygen, produces singlet oxygen, a toxic agent to microorganisms and tumor cells. This study aimed to evaluate singlet oxygen quantum yield of erythrosine solutions illuminated with a halogen light source in comparison to a LED array (control), and the photodynamic effect of erythrosine dye in association with the halogen light source on Streptococcus mutans. Singlet oxygen quantum yield of erythrosine solutions was quantified using uric acid as a chemical-probe in an aqueous solution. The in vitro effect of the photodynamic antimicrobial activity of erythrosine in association with the halogen photopolimerizing light on Streptococcus mutans (UA 159) was assessed during one minute. Bacterial cultures treated with erythrosine alone served as negative control. Singlet oxygen with 24% and 2.8% degradation of uric acid in one minute and a quantum yield of 0.59 and 0.63 was obtained for the erythrosine samples illuminated with the halogen light and the LED array, respectively. The bacterial cultures with erythrosine illuminated with the halogen light presented a decreased number of CFU mL(-1) in comparison with the negative control, with minimal inhibitory concentrations between 0.312 and 0.156mgmL(-1). The photodynamic response of erythrosine induced by the halogen light was capable of killing S. mutans. Clinical trials should be conducted to better ascertain the use of erythrosine in association with halogen light source for the treatment of dental caries. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis by combustion in solution of Zn2TiO4+Ag for photocatalytic and photodynamic applications in the visible

NASA Astrophysics Data System (ADS)

Lopera, A. A.; Velásquez, A. M.; Chavarriaga, E. A.; Ocampo, S.; Zaghete, M. A.; Graminha, M. A.; Garcia, C. P.

2017-12-01

Zn2TiO4 + Ag compounds were synthesized by the solution combustion path seeking to enhance their photocatalytic and photodynamic response in the visible. X-ray diffraction tests confirmed the formation of the phase and the presence of metallic silver. Field emission electron microscopy evidenced the formation of aggregates formed by grains lower than 100nm. The diffuse reflectance tests allowed to detect compound absorption in the visible region and activation energy of 2.8eV. The evaluation of the photocatalytic properties was performed by the degradation of methylene blue while the photodynamic response in biological systems was performed by the antilesihmanicidal response of the compounds in promastigotes of Leishmania amazonensis. Indirect measurement of ROS species confirmed the formation of oxygen singlets and OH radicals of the compounds when subjected to the action of visible light.

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.

Microgel-Encapsulated Methylene Blue for the Treatment of Breast Cancer Cells by Photodynamic Therapy

PubMed Central

Khanal, Anil; Bui, Minh-Phuong Ngoc

2014-01-01

Purpose Photodynamic therapy (PDT) is gaining increasing recognition for breast cancer treatment because it offers local selectivity and reduced toxic side effects compared to radiotherapy and chemotherapy. In PDT, photosensitizer drugs are loaded in different nanomaterials and used in combination with light exposure. However, the most representative issue with PDT is the difficulty of nanomaterials to encapsulate anticancer drugs at high doses, which results in low efficacy of the PDT treatment. Here, we proposed the development of the poly(N-isopropylacrylamide) (PNIPAM) microgel for the encapsulation of methylene blue, an anticancer drug, for its use as breast cancer treatment in MCF-7 cell line. Methods We developed biocompatible microgels based on nonfunctionalized PNIPAM and its corresponding anionically functionalized PNIPAM and polyacrylic acid (PNIPAM-co-PAA) microgel. Methylene blue was used as the photosensitizer drug because of its ability to generate toxic reactive oxygen species upon exposure to light at 664 nm. Core PNIPAM and core/shell PNIPAM-co-PAA microgels were synthesized and characterized using ultraviolet-visible spectroscopy and dynamic light scattering. The effect of methylene blue was evaluated using the MCF-7 cell line. Results Loading of methylene blue in core PNIPAM microgel was higher than that in the core/shell PNIPAM-co-PAA microgel, indicating that electrostatic interactions did not play an important role in loading a cationic drug. This behavior is probably due to the skin layer inhibiting the high uptake of drugs in the PNIPAM-co-PAA microgel. Core PNIPAM microgel effectively retained the cationic drug (i.e., methylene blue) for several hours compared to core/shell PNIPAM-co-PAA and enhanced its photodynamic efficacy in vitro more than that of free methylene blue. Conclusion Our results showed that the employment of core PNIPAM and core/shell PNIPAM-co-PAA microgels enhanced the encapsulation of methylene blue. Core PNIPAM

Microgel-encapsulated methylene blue for the treatment of breast cancer cells by photodynamic therapy.

PubMed

Khanal, Anil; Bui, Minh-Phuong Ngoc; Seo, Seong S

2014-03-01

Photodynamic therapy (PDT) is gaining increasing recognition for breast cancer treatment because it offers local selectivity and reduced toxic side effects compared to radiotherapy and chemotherapy. In PDT, photosensitizer drugs are loaded in different nanomaterials and used in combination with light exposure. However, the most representative issue with PDT is the difficulty of nanomaterials to encapsulate anticancer drugs at high doses, which results in low efficacy of the PDT treatment. Here, we proposed the development of the poly(N-isopropylacrylamide) (PNIPAM) microgel for the encapsulation of methylene blue, an anticancer drug, for its use as breast cancer treatment in MCF-7 cell line. We developed biocompatible microgels based on nonfunctionalized PNIPAM and its corresponding anionically functionalized PNIPAM and polyacrylic acid (PNIPAM-co-PAA) microgel. Methylene blue was used as the photosensitizer drug because of its ability to generate toxic reactive oxygen species upon exposure to light at 664 nm. Core PNIPAM and core/shell PNIPAM-co-PAA microgels were synthesized and characterized using ultraviolet-visible spectroscopy and dynamic light scattering. The effect of methylene blue was evaluated using the MCF-7 cell line. Loading of methylene blue in core PNIPAM microgel was higher than that in the core/shell PNIPAM-co-PAA microgel, indicating that electrostatic interactions did not play an important role in loading a cationic drug. This behavior is probably due to the skin layer inhibiting the high uptake of drugs in the PNIPAM-co-PAA microgel. Core PNIPAM microgel effectively retained the cationic drug (i.e., methylene blue) for several hours compared to core/shell PNIPAM-co-PAA and enhanced its photodynamic efficacy in vitro more than that of free methylene blue. Our results showed that the employment of core PNIPAM and core/shell PNIPAM-co-PAA microgels enhanced the encapsulation of methylene blue. Core PNIPAM microgel released the drug more slowly

Reflectance and fluorescence spectroscopies in photodynamic therapy

NASA Astrophysics Data System (ADS)

Finlay, Jarod C.

In vivo fluorescence spectroscopy during photodynamic therapy (PDT) has the potential to provide information on the distribution and degradation of sensitizers, the formation of fluorescent photoproducts and changes in tissue autofluorescence induced by photodynamic treatment. Reflectance spectroscopy allows quantification of light absorption and scattering in tissue. We present the results of several related studies of fluorescence and reflectance spectroscopy and their applications to photodynamic dosimetry. First, we develop and test an empirical method for the correction of the distortions imposed on fluorescence spectra by absorption and scattering in turbid media. We characterize the irradiance dependence of the in vivo photobleaching of three sensitizers, protoporphyrin IX (PpIX), Photofrin and mTHPC, in a rat skin model. The photobleaching and photoproduct formation of PpIX exhibit irradiance dependence consistent with singlet oxygen (1O2)-mediated bleaching. The bleaching of mTHPC occurs in two phases, only one of which is consistent with a 1O 2-mediated mechanism. Photofrin's bleaching is independent of irradiance, although its photoproduct formation is not. This can be explained by a mixed-mechanism bleaching model. Second, we develop an algorithm for the determination of tissue optical properties using diffuse reflectance spectra measured at a single source-detector separation and demonstrate the recovery of the hemoglobin oxygen dissociation curve from tissue-simulating phantoms containing human erythrocytes. This method is then used to investigate the heterogeneity of oxygenation response in murine tumors induced by carbogen inhalation. We find that while the response varies among animals and within each tumor, the majority of tumors exhibit an increase in blood oxygenation during carbogen breathing. We present a forward-adjoint model of fluorescence propagation that uses the optical property information acquired from reflectance spectroscopy to

Block copolymer nanoassemblies for photodynamic therapy and diagnosis.

PubMed

Dickerson, Matthew; Bae, Younsoo

2013-11-01

Light can be a powerful therapeutic and diagnostic tool. Light-sensitive molecules can be used to develop locally targeted cancer therapeutics. This approach is known as photodynamic therapy (PDT). Similarly, it is possible to diagnose diseases and track the course of treatment in vivo using ligh-sensitive molecules. This methodology is referred to as photodynamic diagnosis (PDD). Despite the potential, many PDT and PDD agents have imperfect physiochemical properties for their successful clinical application. Nanotechnology may solve these issues by improving the viability of PDT and PDD. This review summarizes the current state of PDT and PDD development, the integration of nanotechnology in the field, and the prospective future applications, demonstrating the potential of PDT and PDD for improved cancer treatment and diagnosis.

Gold nanocage-photosensitizer conjugates for dual-modal image-guided enhanced photodynamic therapy.

PubMed

Srivatsan, Avinash; Jenkins, Samir V; Jeon, Mansik; Wu, Zhijin; Kim, Chulhong; Chen, Jingyi; Pandey, Ravindra K

2014-01-01

We have demonstrated that gold nanocage-photosensitizer conjugates can enable dual image-guided delivery of photosensitizer and significantly improve the efficacy of photodynamic therapy in a murine model. The photosensitizer, 3-devinyl-3-(1'-hexyloxyethyl)pyropheophorbide (HPPH), was noncovalently entrapped in the poly(ethylene glycol) monolayer coated on the surface of gold nanocages. The conjugate is stable in saline solutions, while incubation in protein rich solutions leads to gradual unloading of the HPPH, which can be monitored optically by fluorescence and photoacoustic imaging. The slow nature of the release in turn results in an increase in accumulation of the drug within implanted tumors due to the passive delivery of gold nanocages. Furthermore, the conjugate is found to generate more therapeutic singlet oxygen and have a lower IC50 value than the free drug alone. Thus the conjugate shows significant suppression of tumor growth as compared to the free drug in vivo. Short-term study showed neither toxicity nor phenotypical changes in mice at therapeutic dose of the conjugates or even at 100-fold higher than therapeutic dose of gold nanocages.

Expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer.

PubMed

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

2016-03-01

The mechanism underlying the increased levels of protoporphyrin IX in bladder cancer remains unclear. Here, we focus on proteins associated with protoporphyrin IX accumulation in bladder cancer cells and investigate the protein that plays a key role in increased protoporphyrin IX accumulation in bladder cancer cells. Western blotting was used to determine the expression of peptide transporter 1, hydroxymethylbilane synthase, ferrochelatase, ATP-binding cassette 2, and heme oxygenase-1 in bladder cancer cell line cells. We evaluated the correlation between the expression of each protein and accumulated protoporphyrin IX in these cells using Pearson's correlation analysis. Immunohistochemistry was used to estimate the expression of the same five proteins in samples from 75 patients who underwent transurethral resection of bladder tumors. The correlation between the expression of each protein in cells from resected bladder specimens and accumulated protoporphyrin IX in bladder cancer cells in voided urine was evaluated using Pearson's correlation analysis. The expression of ferrochelatase showed a significant negative correlation with protoporphyrin IX accumulation in vitro (p=0.04). The expression of peptide transporter 1 (p<0.01, R=0.39), heme oxygenase-1 (p<0.01, R=0.33), and ferrochelatase (p<0.01, R=0.75) in resected bladder specimens by immunohistochemistry was correlated with protoporphyrin IX accumulation in bladder cancer cells in voided urine. On multivariate analysis, the expression of ferrochelatase (p=0.03) was significant factors to predict positive 5-aminolevulinic acid-induced fluorescent cytology. The expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds

PubMed Central

Caffarel-Salvador, Ester; Kearney, Mary-Carmel; Mairs, Rachel; Gallo, Luigi; Stewart, Sarah A.; Brady, Aaron J.; Donnelly, Ryan F.

2015-01-01

Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed “photodynamic antimicrobial chemotherapy” (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez® AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1–2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for

A double-blind randomized controlled trial to assess the efficacy of daylight photodynamic therapy with methyl-aminolevulinate vs. Placebo and daylight in patients with facial photodamage.

PubMed

Sanclemente, G; Mancilla, G A; Hernandez, G

2016-04-01

Daylight PDT (dPDT) is easy to use and does not require light equipment. Such therapy has been exhaustively proved to be successful in the treatment of actinic keratosis, but its use in skin photodamage remains unclear. To evaluate dPDT's efficacy in skin facial photodamage. This was a parallel-group double-blind, randomized placebo-controlled trial. Sixty participants with symmetric facial photodamage were allocated to topical methyl aminolevulinate (MAL) and daylight vs. matching placebo and daylight. Primary outcome was global photodamage improvement/failure 1 month after the third session. Secondary outcomes included: pain evaluation; specific photodamage severity scores; sun irradiance quantification and Skindex-29 scores. Adverse events were also investigated. Primary analysis included all randomized patients. All patients sun-exposed for 120min in 3 sessions. The risk of failure was lower in the MAL-dPDT group than in the placebo plus daylight group (RR: 0.18; 95% CI: 0.08-0.41). Mean solar irradiance (W/m(2)) during the first, second and third sessions was 480.82, 430.07 and 435.84, respectively. Items 5 and 14 of Skindex-29 in the MAL-dPDT group showed statistical significant differences. Two patients in the MAL-dPDT group had serious and non-serious events not directly related to the product. dPDT with MAL was un-painful, effective and safe for the treatment of facial photodamage. Herpes simplex prophylaxis should be considered before sessions. Copyright © 2015 AEDV. Published by Elsevier España, S.L.U. All rights reserved.

Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy

PubMed Central

Modi, Kshitij D.; Foster, Thomas H.

2013-01-01

Abstract. We demonstrate the use of an enzyme-activatable fluorogenic probe, Neutrophil Elastase 680 FAST (NE680), for in vivo imaging of neutrophil elastase (NE) activity in tumors subjected to photodynamic therapy (PDT). NE protease activity was assayed in SCC VII and EMT6 tumors established in C3H and BALB/c mice, respectively. Four nanomoles of NE680 was injected intravenously immediately following PDT irradiation. 5 h following administration of NE680, whole-mouse fluorescence imaging was performed. At this time point, levels of NE680 fluorescence were at least threefold greater in irradiated versus unirradiated SCC VII and EMT6 tumors sensitized with Photofrin. To compare possible photosensitizer-specific differences in therapy-induced elastase activity, EMT6 tumors were also subjected to 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-PDT. NE levels measured in HPPH-PDT-treated tumors were twofold higher than in unirradiated controls. Ex vivo labeling of host cells using fluorophore-conjugated antibodies and confocal imaging were used to visualize Gr1+ cells in Photofrin-PDT-treated EMT6 tumors. These data were compared with recently reported analysis of Gr1+ cell accumulation in EMT6 tumors subjected to HPPH-PDT. The population density of infiltrating Gr1+ cells in treated versus unirradiated drug-only control tumors suggests that the differential in NE680 fold enhancement observed in Photofrin versus HPPH treatment may be attributed to the significantly increased inflammatory response induced by Photofrin-PDT. The in vivo imaging of NE680, which is a fluorescent reporter of NE extracellular release caused by neutrophil activation, demonstrates that PDT results in increased NE levels in treated tumors, and the accumulation of the cleaved probe tracks qualitatively with the intratumor Gr1+ cell population. PMID:23897439

Study of the Photodynamic Activity of N-Doped TiO2 Nanoparticles Conjugated with Aluminum Phthalocyanine

PubMed Central

Pan, Xiaobo; Liang, Xinyue; Yao, Longfang; Wang, Xinyi; Jing, Yueyue; Fei, Yiyan; Chen, Li

2017-01-01

TiO2 nanoparticles modified with phthalocyanines (Pc) have been proven to be a potential photosensitizer in the application of photodynamic therapy (PDT). However, the generation of reactive oxygen species (ROS) by TiO2 nanoparticles modified with Pc has not been demonstrated clearly. In this study, nitrogen-doped TiO2 conjugated with Pc (N-TiO2-Pc) were studied by means of monitoring the generation of ROS. The absorbance and photokilling effect on HeLa cells upon visible light of different regions were also studied and compared with non-doped TiO2-Pc and Pc. Both N-TiO2-Pc and TiO2-Pc can be activated by visible light and exhibited much higher photokilling effect on HeLa cells than Pc. In addition, nitrogen-doping can greatly enhance the formation of 1O2 and •O2−, while it suppresses the generation of OH•. This resulted in significant photodynamic activity. Therefore, N-TiO2-Pc can be an excellent candidate for a photosensitizer in PDT with wide-spectrum visible irradiation. PMID:29053580

5-Aminolevulinic Acid-Induced Fluorescence in Cerebellar Primary Central Nervous System Lymphoma: A Case Report and Literature Review.

PubMed

Yamamoto, Junkoh; Kitagawa, Takehiro; Akiba, Daisuke; Nishizawa, Shigeru

2015-01-01

5-Aminolevulinic acid (5-ALA)-induced fluorescence-guided resection is a widely used procedure for patients with malignant gliomas. However, the clinical application of 5-ALA for surgery in primary central nervous system lymphoma (PCNSL) is uncommon. Here, we present a case of PCNSL treated using 5-ALA-induced fluorescence-guided resective surgery. A 70-year-old woman presented with cerebellar ataxia, and magnetic resonance imaging revealed an irregularly shaped and homogenously enhanced mass with surrounding brain edema in the vermis that extended to the right hemisphere of the cerebellum. Under the preoperative diagnosis of a malignant glioma in the cerebellum, the patient underwent 5-ALA-induced fluorescence-guided surgery. Under blue light illumination, the tumor revealed strong 5-ALA-induced fluorescence. The tumor was identified as a diffuse large B-cell lymphoma. After partial resection, the patient received adjuvant chemotherapy and radiotherapy. Importantly, the neurological deficit of the patient improved, and recurrence of the tumor was not observed 21 months post-surgery. Together with previous reports, this case study emphasizes the efficacy of the surgical application of 5-ALA for PCNSL.

Photodynamic therapy for inactivating endodontic bacterial biofilms and effect of tissue inhibitors on antibacterial efficacy

NASA Astrophysics Data System (ADS)

Shrestha, Annie; Kishen, Anil

Complex nature of bacterial cell membrane and structure of biofilm has challenged the efficacy of antimicrobial photodynamic therapy (APDT) to achieve effective disinfection of infected root canals. In addition, tissue-inhibitors present inside the root canals are known to affect APDT activity. This study was aimed to assess the effect of APDT on bacterial biofilms and evaluate the effect of tissue-inhibitors on the APDT. Rose-bengal (RB) and methylene-blue (MB) were tested on Enterococcus faecalis (gram-positive) and Pseudomonas aeruginosa (gram-negative) biofilms. In vitro 7- day old biofilms were sensitized with RB and MB, and photodynamically activated with 20-60 J/cm2. Photosensitizers were pre-treated with different tissue-inhibitors (dentin, dentin-matrix, pulp tissue, bacterial lipopolysaccharides (LPS), and bovine serum albumin (BSA)) and tested for antibacterial effect of APDT. Microbiological culture based analysis was used to analyze the cell viability, while Laser Scanning Confocal Microscopy (LSCM) was used to examine the structure of biofilm. Photoactivation resulted in significant reduction of bacterial biofilms with RB and MB. The structure of biofilm under LSCM was found to be disrupted with reduced biofilm thickness. Complete biofilm elimination could not be achieved with both tested photosensitizers. APDT effect using MB and RB was inhibited in a decreasing order by dentin-matrix, BSA, pulp, dentin and LPS (P< 0.05). Both strains of bacterial biofilms resisted complete elimination after APDT and the tissue inhibitors existing within the root canal reduced the antibacterial activity at varying degrees. Further research is required to enhance the antibacterial efficacy of APDT in an endodontic environment.

Photodynamic inactivation of foodborne bacteria by eosin Y.

PubMed

Bonin, E; Dos Santos, A R; Fiori da Silva, A; Ribeiro, L H; Favero, M E; Campanerut-Sá, P A Z; de Freitas, C F; Caetano, W; Hioka, N; Mikcha, J M G

2018-06-01

The aim of this study was evaluate the effect of photodynamic inactivation mediated by eosin Y in Salmonella enterica serotype Typhimurium ATCC 14028, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 and Bacillus cereus ATCC 11778. Bacteria (10 7 CFU per ml) were incubated with eosin Y at concentrations ranging from 0·1 to 10 μmol l -1 , irradiated by green LED (λ max 490-570 nm) for 5, 10 and 15 min and the cellular viability was determined. Pseudomonas aeruginosa was completely inactivated when treated with 10 μmol l -1 eosin Y for 10 min. Treatments reduced B. cereus and Salm. Typhimurium counts to 2·7 log CFU per ml and 1·7 log CFU per ml, respectively. Escherichia coli counts were slightly reduced. Staphylococcus aureus presented the highest sensitivity, being completely inactivated by eosin Y at 5 μmol l -1 and 5 min of illumination. The reduction of cellular viability of photoinactivated Staph. aureus was also demonstrated by flow cytometry and morphological changes were observed by scanning electron microscopy. Eosin Y in combination with LED produced bacterial inactivation, being a potential candidate for photodynamic inactivation. This study evidenced the efficacy of photodynamic inactivation as a novel and promising alternative to bacterial control. © 2018 The Society for Applied Microbiology.

Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer.

PubMed

Korbelik, M; Naraparaju, V R; Yamamoto, N

1997-01-01

The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours.

Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer.

PubMed Central

Korbelik, M.; Naraparaju, V. R.; Yamamoto, N.

1997-01-01

The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours. PMID:9010027

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Antitumor effects evaluation of a novel porphyrin derivative in photodynamic therapy.

PubMed

Li, Jian-Wei; Wu, Zhong-Ming; Magetic, Davor; Zhang, Li-Jun; Chen, Zhi-Long

2015-12-01

In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

Photodynamic therapy for polypoidal choroidal vasculopathy secondary to choroidal nevus.

PubMed

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.

Photodynamic treatment of herpes simplex virus during its replicative cycle.

PubMed Central

Khan, N C; Melnick, J L; Biswal, N

1977-01-01

Photodynamic treatment of herpes simplex virus type 1-infected hamster embryo fibroblasts (LSH strain) with a low concentration of proflavine (0.08 mug/10(5) cells per ml), a 3-9-diamine acridine dye, inhibited production not only of infectious progeny but also of virion particles. However, there was no appreciable inhibition of viral or cellular DNA synthesis, even when the infected cells were repeatedly exposed to this low concentration of dye and light during the replication cycle of the virus. It thus appears that photodynamic treatment of infected cells interferes with the processes involved in virus maturation. PMID:189063

δ-Aminolevulinic Acid Dehydratase Single Nucleotide Polymorphism 2 (ALAD2) and Peptide Transporter 2*2 Haplotype (hPEPT2*2) Differently Influence Neurobehavior in Low-Level Lead Exposed Children

PubMed Central

Sobin, Christina; Gisel Flores-Montoya, Mayra; Gutierrez, Marisela; Parisi, Natali; Schaub, Tanner

2014-01-01

Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1 to 11.8 years. Ninety-six percent of children had BLLs < 5.0 µg/dL. After adjusting for covariates (sex, age and mother’s level of education) and sibling exclusion (N = 252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior. PMID:25514583

δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobehavior in low-level lead exposed children.

PubMed

Sobin, Christina; Flores-Montoya, Mayra Gisel; Gutierrez, Marisela; Parisi, Natali; Schaub, Tanner

2015-01-01

Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLs<5.0μg/dl. After adjusting for covariates (sex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis of an acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, Luc

1999-01-01

A process of preparing an acid addition salt of delta-aminolevulinic acid comprising: dissolving a lower alkyl 5-bromolevulinate and an alkali metal diformylamide in an organic solvent selected from the group consisting of acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran and methylformate or mixtures thereof to form a suspension of an alkyl 5-(N,N-diformylamino) levulinate ester; and hydrolyzing said alkyl 5-(N,N-diformylamino) levulinate with an inorganic acid to form an acid addition salt of delta-amino levulinic acid.

Enhancing photodynamic therapy of a metastatic mouse breast cancer by immune stimulation

NASA Astrophysics Data System (ADS)

Castano, Ana P.; Hamblin, Michael R.

2006-02-01

One in 8 women in the United States will develop breast cancer during her lifetime and 40,000 die each year. Deaths are due to tumors that have metastasized despite local control. Photodynamic therapy (PDT) is a promising cancer treatment in which a photosensitizer (PS) accumulates in tumors and is subsequently activated by visible light of an appropriate wavelength. The energy of the light is transferred to molecular oxygen to produce reactive oxygen species that produce cell death and tumor ablation. Mechanisms include cytotoxicity to tumor cells, shutting down of the tumor vasculature, and the induction of a host immune response. The precise mechanisms involved in the PDT-mediated induction of anti-tumor immunity are not yet understood. Potential contributing factors are alterations in the tumor microenvironment via stimulation of proinflammatory cytokines and direct effects of PDT on the tumor that increase immunogenicity. We have studied PDT of 410.4 variant 4T1 tumors growing in the mammary fat pad (orthotopic) in Balb/c mice and which produce metastasis. We have shown that a PDT regimen that produces vascular shutdown and tumor necrosis leads to initial tumor ablation but the tumors recur at the periphery. We studied the combination of PDT with immunostimulating therapies. Low dose cyclophosphamide (CY) is a specific mechanism to deplete the regulatory T cells (CD4+CD25+), these cells play an important role in the immunosuppression activity of tumors. In combination with PDT that produces release of tumor specific antigens, this immunostimulation may lead to generation of cytotoxic CD8 T-lymphocytes that recognize and destroy the tumor. The second alternative therapy is the use of a novel combination of the immunostimulant CpG oligodeoxynucleotides (CpG-ODN) and PDT. CpG-ODN is recognized by Toll-like receptor 9 and directly or indirectly triggers B cells, NK cells, monocyte-macrophages and dendritic cells to proliferate, mature and secrete cytokines

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.

Photosensitizer and peptide-conjugated PAMAM dendrimer for targeted in vivo photodynamic therapy.

PubMed

Narsireddy, Amreddy; Vijayashree, Kurra; Adimoolam, Mahesh G; Manorama, Sunkara V; Rao, Nalam M

2015-01-01

Challenges in photodynamic therapy (PDT) include development of efficient near infrared-sensitive photosensitizers (5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphine [PS]) and targeted delivery of PS to the tumor tissue. In this study, a dual functional dendrimer was synthesized for targeted PDT. For targeting, a poly(amidoamine) dendrimer (G4) was conjugated with a PS and a nitrilotriacetic acid (NTA) group. A peptide specific to human epidermal growth factor 2 was expressed in Escherichia coli with a His-tag and was specifically bound to the NTA group on the dendrimer. Reaction conditions were optimized to result in dendrimers with PS and the NTA at a fractional occupancy of 50% and 15%, respectively. The dendrimers were characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization, absorbance, and fluorescence spectroscopy. Using PS fluorescence, cell uptake of these particles was confirmed by confocal microscopy and fluorescence-activated cell sorting. PS-dendrimers are more efficient than free PS in PDT-mediated cell death assays in HER2 positive cells, SK-OV-3. Similar effects were absent in HER2 negative cell line, MCF-7. Compared to free PS, the PS-dendrimers have shown significant tumor suppression in a xenograft animal tumor model. Conjugation of a PS with dendrimers and with a targeting agent has enhanced photodynamic therapeutic effects of the PS.

Photosensitizer and peptide-conjugated PAMAM dendrimer for targeted in vivo photodynamic therapy

PubMed Central

Narsireddy, Amreddy; Vijayashree, Kurra; Adimoolam, Mahesh G; Manorama, Sunkara V; Rao, Nalam M

2015-01-01

Challenges in photodynamic therapy (PDT) include development of efficient near infrared-sensitive photosensitizers (5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphine [PS]) and targeted delivery of PS to the tumor tissue. In this study, a dual functional dendrimer was synthesized for targeted PDT. For targeting, a poly(amidoamine) dendrimer (G4) was conjugated with a PS and a nitrilotriacetic acid (NTA) group. A peptide specific to human epidermal growth factor 2 was expressed in Escherichia coli with a His-tag and was specifically bound to the NTA group on the dendrimer. Reaction conditions were optimized to result in dendrimers with PS and the NTA at a fractional occupancy of 50% and 15%, respectively. The dendrimers were characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization, absorbance, and fluorescence spectroscopy. Using PS fluorescence, cell uptake of these particles was confirmed by confocal microscopy and fluorescence-activated cell sorting. PS-dendrimers are more efficient than free PS in PDT-mediated cell death assays in HER2 positive cells, SK-OV-3. Similar effects were absent in HER2 negative cell line, MCF-7. Compared to free PS, the PS-dendrimers have shown significant tumor suppression in a xenograft animal tumor model. Conjugation of a PS with dendrimers and with a targeting agent has enhanced photodynamic therapeutic effects of the PS. PMID:26604753

Near-infrared photodynamic inactivation of S. pneumoniae and its interaction with RAW 264.7 macrophages.

PubMed

Leite, Ilaiáli S; Geralde, Mariana C; Salina, Ana C G; Medeiros, Alexandra I; Dovigo, Lívia N; Bagnato, Vanderlei S; Inada, Natalia M

2018-01-01

Pneumonia is the main cause of children mortality worldwide, and its major treatment obstacle stems from the microorganisms increasing development of resistance to several antibiotics. Photodynamic therapy has been presenting, for the last decades, promising results for some subtypes of cancer and infections. In this work we aimed to develop a safe and efficient in vitro protocol for photodynamic inactivation of Streptococcus pneumoniae, one of the most commonly found bacteria in pneumonia cases, using two near-infrared light sources and indocyanine green, a FDA approved dye. Photodynamic inactivation experiments with bacteria alone allowed to determine the best parameters for microbial inactivation. Cytotoxicity assays with RAW 264.7 macrophages evaluated the safety of the PDI. To determine if the photodynamic inactivation had a positive or negative effect on the natural killing action of macrophages, we selected and tested fewer indocyanine green concentrations and 10 J/cm 2 on macrophage-S. pneumoniae co-cultures. We concluded that ICG has potential as a photosensitizer for near-infrared photodynamic inactivation of S. pneumoniae, producing minimum negative impact on RAW 264.7 macrophages and having a positive interaction with the immune cell's microbicidal action. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Noninvasive extramammary Paget's disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute.

PubMed

Housel, Joseph P; Izikson, Leonid; Zeitouni, Nathalie C

2010-11-01

Extramammary Paget's disease (EMPD) is a rare low-grade cutaneous malignancy that affects apocrine gland-bearing areas and most commonly occurs on the perineal skin. Photodynamic therapy (PDT) may represent a useful treatment option for extensive, noninvasive EMPD, alone or as part of multimodal therapy. To analyze the clinical outcomes of PDT for noninvasive EMPD with topical aminolevulinic acid (ALA) or intravenous porfimer sodium as photosensitizing agents and argon laser as the photoactivator. Retrospective case series of patients with noninvasive EMPD treated at Roswell Park Cancer Institute with PDT from April 20, 1995, to December 4, 2008. Identified patients included five men and three women aged 50 to 80 (mean age 67) with a total of 24 distinct lesions of noninvasive EMPD without distant metastases. Four patients received topical ALA only as a photosensitizer, three received intravenous porfimer sodium only, and one received both. All patients were treated using a 632.8-nm argon-pumped dye laser, and some were also treated using a red lamp (590-729 nm). Seven of nine lesions (78%) treated with PDT using intravenous porfimer sodium showed a complete response (CR) and were disease free at 12 to 96 months. Eight of 16 lesions (50%) treated with PDT using topical ALA showed a CR, and 38% were disease free at 9 to 88 months. None of the treated patients developed any serious cosmetic or functional impairments, such as loss of sphincter control or dysesthesias. PDT with intravenous porfimer sodium or topical ALA and argon laser may represent a useful, surgery-sparing therapeutic option for management of noninvasive EMPD in selected patients. Prospective, randomized clinical trials are necessary to compare the effectiveness of PDT with that of surgery for noninvasive EMPD. © 2010 by the American Society for Dermatologic Surgery, Inc.

Photodynamic therapy for premalignant lesions of the vulva and vagina: A long-term follow-up study.

PubMed

Choi, Min Chul; Kim, Mi Sun; Lee, Gee Hoon; Jung, Sang Geun; Park, Hyun; Joo, Won Duk; Lee, Chan; Lee, Je Ho; Hwang, Yoon Young; Kim, Seung Jo

2015-07-14

We aimed to evaluate responses to photodynamic therapy (PDT) and its long-term efficacy in preserving normal anatomy and function in women with premalignant lesions of the lower genital tract. Fifteen patients received PDT for vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), or vulvar Paget's disease between January 2003 and December 2013. Patients underwent colposcopy and/or vulvoscopy for assessment of lesions. Surface photoillumination with a 630-nm red laser light was applied to the lesions 48 hours after intravenous injection of 2 mg/kg photosensitizer (PSZ; Photogem®). The light dose to the lesions was 150 J/cm 2 . The median age of the 15 patients (VIN II: 3, VIN III: 4, VAIN II: 2, VAIN III: 3, Paget's disease: 3) was 42.3 years. The complete response (CR) rate was 80% (12/15) at the 3-month follow-up and 71.4% (10/14) at the 1-year follow-up. There were two cases of persistent disease at the 3-month follow-up. One patient with persistent disease underwent partial vulvectomy three times for repetitive recurrence, and the other received secondary PDT with topical 5-aminolevulinic acid (5-ALA) and subsequently showed no evidence of disease (NED). Another patient achieved 90% remission through a combination of additional alternative treatments after showing partial response (PR). In two cases of CR, recurrence was observed at the 1-year follow-up. Regarding adverse events, photosensitivity reactions such as facial edema and urticaria occurred in 13.3% (2/15) and perineal pain occurred in one patient. PDT may be an effective alternative treatment for premalignant lesions of the female lower genital tract to preserve normal anatomy and sexual function without therapeutic impairment. Lasers Surg. Med. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors

PubMed Central

Jaber, Mohammed; Wölfer, Johannes; Ewelt, Christian; Holling, Markus; Hasselblatt, Martin; Niederstadt, Thomas; Zoubi, Tarek; Weckesser, Matthias

2015-01-01

BACKGROUND: Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. OBJECTIVE: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [18F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. METHODS: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and 18F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. RESULTS: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and 18F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. CONCLUSION: Age, tumor volume, and 18F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased

Photodynamic antimicrobial chemotherapy using zinc phthalocyanine derivatives in treatment of bacterial skin infection

NASA Astrophysics Data System (ADS)

Chen, Zhuo; Zhang, Yaxin; Wang, Dong; Li, Linsen; Zhou, Shanyong; Huang, Joy H.; Chen, Jincan; Hu, Ping; Huang, Mingdong

2016-01-01

Photodynamic antimicrobial chemotherapy (PACT) is an effective method for killing bacterial cells in view of the increasing problem of multiantibiotic resistance. We herein reported the PACT effect on bacteria involved in skin infections using a zinc phthalocyanine derivative, pentalysine β-carbonylphthalocyanine zinc (ZnPc-Lys). Compared with its anionic ZnPc counterpart, ZnPc-Lys showed an enhanced antibacterial efficacy in vitro and in an animal model of localized infection. Meanwhile, ZnPc-Lys was observed to significantly reduce the wound skin blood flow during wound healing, indicating an anti-inflammation activity. This study provides new insight on the mechanisms of PACT in bacterial skin infection.

delta. -aminolevulinic acid dehydratase deficiency can cause. delta. -aminolevulinate auxotrophy in Escherichia coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neill, G.P.; Michelsen, U.; Soll, D.

Ethylmethane sulfonate-induced mutants of several Escherichia coli strains that required {delta}-aminolevulinic acid (ALA) for growth were isolated by penicillin enrichment or by selection for respiratory-defective strains resistant to the aminoglycoside antibiotic kanamycin. Three classes of mutants were obtained. Two-thirds of the strains were mutants in hemA. Representative of a third of the mutations was the hem-201 mutation. This mutation was mapped to min 8.6 to 8.7. Complementation of the auxotrophic phenotype by wild-type DNA from the corresponding phage 8F10 allowed the isolation of the gene. DNA sequence analysis revealed that the hem-201 gene encoded ALA dehydratase and was similar tomore » a known hemB gene of E. coli. Complementation studies of hem-201 and hemB1 mutant strains with various hem-201 gene subfragments showed that hem-201 and the previously reported hemB1 mutation are in the same gene and that no other gene is required to complement the hem-201 mutant. ALA-forming activity from glutamate could not be detected by in vitro or in vivo assays. Extracts of hem-201 cells had drastically reduce ALA dehydratase levels, while cells transformed with the plasmid-encoded wild-type gene possessed highly elevated enzyme levels. The ALA requirement for growth, the lack of any ALA-forming enzymatic activity, and greatly reduced ALA dehydratase activity of the hem-201 strain suggest that a diffusible product of an enzyme in the heme biosynthetic pathway after ALA formation is involved in positive regulation of ALA biosynthesis. Analysis of another class of ALA-requiring mutants showed that the auxotrophy of the hem-205 mutant could be relieved by either methionine or cysteine and that the mutation maps in the cysG gene, which encodes uroporphyrinogen III methylase. The properties of these nonleaky ALA-requiring strains suggest that ALA is involved more extensively in E. coli intermediary metabolism than has been appreciated to date.« less

Synthesis of an acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, L.

1999-05-25

A process is disclosed for preparing an acid addition salt of delta-aminolevulinic acid comprising. The process involves dissolving a lower alkyl 5-bromolevulinate and an alkali metal diformylamide in an organic solvent selected from the group consisting of acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran and methylformate or mixtures to form a suspension of an alkyl 5-(N,N-diformylamino) levulinate ester; and hydrolyzing the alkyl 5-(N,N-diformylamino) levulinate with an inorganic acid to form an acid addition salt of delta-amino levulinic acid.

Combination of photothermal and photodynamic inactivation of cancer cells through surface plasmon resonance of a gold nanoring

NASA Astrophysics Data System (ADS)

Chu, Chih-Ken; Tu, Yi-Chou; Hsiao, Jen-Hung; Yu, Jian-He; Yu, Chih-Kang; Chen, Shih-Yang; Tseng, Po-Hao; Chen, Shuai; Kiang, Yean-Woei; Yang, C. C.

2016-03-01

We demonstrate effective inactivation of oral cancer cells SAS through a combination of photothermal therapy (PTT) and photodynamic therapy (PDT) effects based on localized surface plasmon resonance (LSPR) around 1064 nm in wavelength of a Au nanoring (NRI) under femtosecond (fs) laser illumination. The PTT effect is caused by the LSPR-enhanced absorption of the Au NRI. The PDT effect is generated by linking the Au NRI with the photosensitizer of sulfonated aluminum phthalocyanines (AlPcS) for producing singlet oxygen through the LSPR-enhanced two-photon absorption (TPA) excitation of AlPcS. The laser threshold intensity for cancer cell inactivation with the applied Au NRI linked with AlPcS is significantly lower when compared to that with the Au NRI not linked with AlPcS. The comparison of inactivation threshold intensity between the cases of fs and continuous laser illuminations at the same wavelength and with the same average power confirms the crucial factor of TPA under fs laser illumination for producing the PDT effect.

The effects of photodynamic laser therapy in the treatment of marginal chronic periodontitis

NASA Astrophysics Data System (ADS)

Chifor, Radu; Badea, Iulia; Avram, Ramona; Chifor, Ioana; Badea, Mîndra Eugenia

2016-03-01

The aim of this study was to assess the effects of the antimicrobial photodynamic laser therapy performed during the treatment of deep periodontal disease by using 40 MHz high frequency ultrasonography. The periodontal data recorded during the clinical examination before each treatment session were compared with volumetric changes of the gingiva measured on periodontal ultrasound images. The results show a significant decrease of gingival tissue inflammation proved both by a significant decrease of bleeding on probing as well as by a decrease of the gingival tissues volume on sites where the laser therapy was performed. Periodontal tissues that benefit of laser therapy besides classical non-surgical treatment showed a significant clinical improvement of periodontal status. Based on these findings we were able to conclude that the antimicrobial photodynamic laser therapy applied on marginal periodontium has important anti-inflamatory effect. The periodontal ultrasonography is a method which can provide useful data for assessing the volume changes of gingival tissues, allowing a precise monitoring of marginal periodontitis.

A supramolecular photosensitizer system based on the host-guest complexation between water-soluble pillar[6]arene and methylene blue for durable photodynamic therapy.

PubMed

Yang, Kui; Wen, Jia; Chao, Shuang; Liu, Jing; Yang, Ke; Pei, Yuxin; Pei, Zhichao

2018-06-05

A supramolecular photosensitizer system WP6-MB was synthesized based on water-soluble pillar[6]arene and the photosensitizer methylene blue (MB) via host-guest interaction. MB can complex with WP6 directly with a high complex constant without further modification. In particular, WP6-MB can reduce the dark toxicity of MB remarkably. Furthermore, it can efficiently overcome photobleaching and extend the time for singlet oxygen production of MB upon light irradiation, which is significant for durable photodynamic therapy.

Development of therapeutic Au-methylene blue nanoparticles for targeted photodynamic therapy of cervical cancer cells.

PubMed

Yu, Jiashing; Hsu, Che-Hao; Huang, Chih-Chia; Chang, Po-Yang

2015-01-14

Photodynamic therapy (PDT) involves the cellular uptake of a photosensitizer (PS) combined with oxygen molecules and light at a specific wavelength to be able to trigger cancer cell death via the apoptosis pathway, which is less harmful and has less inflammatory side effect than necrosis. However, the traditional PDT treatment has two main deficiencies: the dark toxicity of the PS and the poor selectivity of the cellular uptake of PS between the target cells and normal tissues. In this work, methylene blue (MB), a known effective PS, combined with Au nanoparticles (NPs) was prepared using an intermolecular interaction between a polystyrene-alt-maleic acid (PSMA) layer on the Au NPs and MB. The Au@polymer/MB NPs produced a high quantum yield of singlet oxygen molecules, over 50% as much as that of free MB, when they were excited by a dark red light source at 660 nm, but without significant dark toxicity. Furthermore, transferrin (Tf) was conjugated on the Au@polymer/MB NPs via an EDC/NHS reaction to enhance the selectivity to HeLa cells compared to 3T3 fibroblasts. With a hand-held single laser treatment (32 mW/cm) for 4 min, the new Au@polymer/MB-Tf NPs showed a 2-fold enhancement of PDT efficiency toward HeLa cells over the use of free MB at 4 times dosage. Cellular staining examinations showed that the HeLa cells reacted with Au@polymer/MB-Tf NPs and the 660 nm light excitation triggered PDT, which caused the cells to undergo apoptosis ("programmed" cell death). We propose that applying this therapeutic Au@polymer/MB-Tf nanoagent is facile and safe for delivery and cancer cell targeting to simultaneously minimize side effects and accomplish a significant enhancement in photodynamic therapeutic efficiency toward next-generation nanomedicine development.

Apoptosis triggered by pyropheophorbide-α methyl ester-mediated photodynamic therapy in a giant cell tumor in bone

NASA Astrophysics Data System (ADS)

Li, K.-T.; Zhang, J.; Duan, Q.-Q.; Bi, Y.; Bai, D.-Q.; Ou, Y.-S.

2014-06-01

A giant cell tumor in bone is the common primary bone tumor with aggressive features, occurring mainly in young adults. Photodynamic therapy is a new therapeutic technique for tumors. In this study, we investigated the effects of Pyropheophorbide-α methyl ester (MPPa)-mediated photodynamic therapy on the proliferation of giant cell tumor cells and its mechanism of action. Cell proliferation was evaluated using an MTT assay. Cellular apoptosis was detected by Hoechst nuclear staining, and flow cytometric assay. Mitochondrial membrane potential changes and cytochrome c, caspase-9, caspase-3, and Bcl-2 expression was assessed. Finally, we found that MPPa-mediated photodynamic therapy could effectively suppress the proliferation of human giant cell tumor cells and induce apoptosis. The mitochondrial pathway was involved in the MPPa-photodynamic therapy-induced apoptosis.

Light emitting fabric technologies for photodynamic therapy.

PubMed

Mordon, Serge; Cochrane, Cédric; Tylcz, Jean Baptiste; Betrouni, Nacim; Mortier, Laurent; Koncar, Vladan

2015-03-01

Photodynamic therapy (PDT) is considered to be a promising method for treating various types of cancer. A homogeneous and reproducible illumination during clinical PDT plays a determinant role in preventing under- or over-treatment. The development of flexible light sources would considerably improve the homogeneity of light delivery. The integration of optical fiber into flexible structures could offer an interesting alternative. This paper aims to describe different methods proposed to develop Side Emitting Optical Fibers (SEOF), and how these SEOF can be integrated in a flexible structure to improve light illumination of the skin during PDT. Four main techniques can be described: (i) light blanket integrating side-glowing optical fibers, (ii) light emitting panel composed of SEOF obtained by micro-perforations of the cladding, (iii) embroidery-based light emitting fabric, and (iv) woven-based light emitting fabric. Woven-based light emitting fabrics give the best performances: higher fluence rate, best homogeneity of light delivery, good flexibility. Copyright © 2014 Elsevier B.V. All rights reserved.

The cost-utility of photodynamic therapy in eyes with neovascular macular degeneration--a value-based reappraisal with 5-year data.

PubMed

Brown, Gary C; Brown, Melissa M; Campanella, Joseph; Beauchamp, George R

2005-10-01

To assess the value conferred by photodynamic therapy (PDT) and the cost-utility of PDT for the treatment of classic, subfoveal choroidal neovascularization associated with age-related macular degeneration (ARMD). Average cost-utility analysis utilizing clinical trial data, patient-based time tradeoff utility preferences, and a third party insurer cost perspective. Five-year visual acuity data from the TAP (Treatment of Age-related Macular Degeneration With Photodynamic Therapy) Investigation were modeled into a 12-year, value-based, reference case, cost-utility model utilizing year 2004 Medicare costs and an outcome of dollar/QALY (dollars/quality-adjusted life-year). Discounting of outcomes and costs using net present value analysis with a 3% annual rate was performed as recommended by the Panel for Cost-Effectiveness in Health and Medicine. PDT with verteporfin (Visudyne) dye for classic subfoveal choroidal neovascularization confers an 8.1% quality of life (value) improvement over the 12-year life expectancy of the reference case, while during the last 8 years the value improvement is 9.5%. The average cost-utility of the intervention is dollar 31,103/QALY (quality-adjusted life-year). Extensive one-way sensitivity analysis values range from dollar 20,736/QALY if treatment efficacy is increased by 50% to dollar 62,207 if treatment efficacy is decreased by 50%, indicating robustness of the model. PDT using verteporfin dye to treat classic subfoveal choroidal neovascularization is a very cost-effective treatment by conventional standards. The marked improvement in cost-effectiveness compared with a previous report results from the facts that the treatment benefit increasingly accrues during 5 years of follow-up while the number of yearly treatments diminishes markedly during that time.

Zinc phthalocyanines attached to gold nanorods for simultaneous hyperthermic and photodynamic therapies against melanoma in vitro.

PubMed

Freitas, L F; Hamblin, M R; Anzengruber, F; Perussi, J R; Ribeiro, A O; Martins, V C A; Plepis, A M G

2017-08-01

Studies indicate that hyperthermic therapy using gold nanorods and photodynamic activity with many photosensitizers can present a synergistic effect, and offer a great therapeutic potential, although more investigation needs to be performed before such approach could be implemented. We proposed to investigate the effect of the attachment of phthalocyanines on the surface of gold nanorods (well-characterized devices for hyperthermia generation) for the elimination of melanoma, one of the most important skin cancers due to its high lethality. Following the synthesis of nanorods through a seed-mediated method, the efficacy of photodynamic therapy (PDT) and hyperthermia was assessed separately. We chose to coat the nanorods with two tetracarboxylated zinc phthalocyanines - with or without methyl-glucamine groups. After the coating process, the phthalocyanines formed ionic complexes with the cetyltrimethylammonium bromide (CTAB) that was previously covering the nanoparticles. The nanorod-phthalocyanines complexes were analyzed by transmission electron microscopy (TEM), and their singlet oxygen and hydroxyl radical generation yields were assessed. Furthermore, they were tested in vitro with melanotic B16F10 and amelanotic B16G4F melanoma cells. The cells with nanoparticles were irradiated with laser (at 635nm), and the cell viability was assessed. The results indicate that the photodynamic properties of the phthalocyanines tested are enhanced when they are attached on the nanorods surface, and the combination of PDT and hyperthermia was able to eliminate over 90% of melanoma cells. This is a novel study because two tetracarboxylated phthalocyanines were used and because the same wavelength was irradiated to activate both the nanorods and the photosensitizers. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

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. PMID:26151364

Methylene blue, curcumin and ion pairing nanoparticles effects on photodynamic therapy of MDA-MB-231 breast cancer cell.

PubMed

Hosseinzadeh, Reza; Khorsandi, Khatereh

2017-06-01

The aim of current study was to use methylene blue-curcumin ion pair nanoparticles and single dyes as photosensitizer for comparison of photodynamic therapy (PDT) efficacy on MDA-MB-231 cancer cells, also various light sources effect on activation of photosensitizer (PS) was considered. Ion pair nanoparticles were synthesized using opposite charge ions precipitation and lyophilized. The PDT experiments were designed and the effect of PSs and light sources (Red LED (630nm; power density: 30mWcm -2 ) and blue LED (465nm; power density: 34mWcm -2 )) on the human breast cancer cell line were examined. The effect of PS concentration (0-75μg.mL -1 ), incubation time, irradiation time and light sources, and priority in irradiation of blue or red lights were determined. The results show that the ion pairing of methylene blue and curcumin enhance the photodynamic activity of both dyes and the cytotoxicity of ion pair nanoparticles on the MDA-231 breast cancer cell line. Blue and red LED light sources were used for photo activation of photosensitizers. The results demonstrated that both dyes can activate using red light LED better than blue light LED for singlet oxygen producing. Nano scale ion pair precipitating of methylene blue-curcumin enhanced the cell penetrating and subsequently cytotoxicity of both dyes together. Copyright © 2017 Elsevier B.V. All rights reserved.

Non-monotonic changes in clonogenic cell survival induced by disulphonated aluminum phthalocyanine photodynamic treatment in a human glioma cell line

PubMed Central

2010-01-01

Background Photodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes. The ROS, thus produced can cause damage to both the structure and the function of the cellular constituents resulting in cell death. Our preliminary investigations of dose-response relationships in a human glioma cell line (BMG-1) showed that disulphonated aluminum phthalocyanine (AlPcS2) photodynamically induced loss of cell survival in a concentration dependent manner up to 1 μM, further increases in AlPcS2concentration (>1 μM) were, however, observed to decrease the photodynamic toxicity. Considering the fact that for most photosensitizers only monotonic dose-response (survival) relationships have been reported, this result was unexpected. The present studies were, therefore, undertaken to further investigate the concentration dependent photodynamic effects of AlPcS2. Methods Concentration-dependent cellular uptake, sub-cellular localization, proliferation and photodynamic effects of AlPcS2 were investigated in BMG-1 cells by absorbance and fluorescence measurements, image analysis, cell counting and colony forming assays, flow cytometry and micronuclei formation respectively. Results The cellular uptake as a function of extra-cellular AlPcS2 concentrations was observed to be biphasic. AlPcS2 was distributed throughout the cytoplasm with intense fluorescence in the perinuclear regions at a concentration of 1 μM, while a weak diffuse fluorescence was observed at higher concentrations. A concentration-dependent decrease in cell proliferation with accumulation of cells in G2+M phase was observed after PDT. The response of clonogenic survival after AlPcS2-PDT was non-monotonic with respect to AlPcS2 concentration. Conclusions Based on the results we conclude that concentration-dependent changes in physico-chemical properties of sensitizer

Potential role of photodynamic techniques combined with new generation flexible ureterorenoscopes and molecular markers for the management of urothelial carcinoma of the upper urinary tract.

PubMed

Audenet, François; Traxer, Olivier; Yates, David R; Cussenot, Olivier; Rouprêt, Morgan

2012-02-01

•  To discuss how the development of new generation flexible ureterorenoscopes in combination with photodynamic diagnosis (PDD) improves the assessment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC). •  Ultimately, this may allow accurate tumour classification and the ability to select which patients would benefit from conservative treatment as opposed to radical surgery. •  We conducted an exhaustive Pubmed literature search using a combination of keywords including: ureterorenoscopy, UUT-UCC diagnosis, PDD, narrow band imaging, conservative treatment UUT-UCC and molecular urinalysis. •  We then selected salient high calibre articles relevant to our objective. •  We give specific consideration to anatomical aspects of UUT-UCC investigation, PDD in UCC, aminolevulinic acid and its derivatives, autofluorescence, narrow band imaging, molecular marker analysis and the recent advances in ureterorenoscopic technology. •  The traditional pitfalls of UUT-UCC diagnosis, namely poor visualisation and difficulty in obtaining representative histological samples, are being circumvented by the introduction of modern digital flexible ureteroscopes that can be combined with PDD and molecular analysis to improve tumour classification, deferring to conservative treatment accordingly. •  The accuracy of the diagnostic work-up of UUT-UCC is improving due to advances in technology, pharmaceutical agents and incorporation of molecular markers, all factors allowing us to characterise tumours of the UUT more definitively. © 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.

The apoptosis induced by HMME-based photodynamic therapy in rabbit vascular smooth muscle cells

NASA Astrophysics Data System (ADS)

Yin, Huijuan; Li, Xiaoyuan; Lin, Hong; Liu, Jianzhong; Yu, Hongkui

2007-02-01

Objective To study the effects of HMME-based photodynamic therapy on proliferation and apoptosis of rabbit vascular smooth muscle cells(VSMCs). Method The cytotoxic effect of HMME-PDT on rabbit vascular smooth muscle cells was studied by means of Trypan Blue assay, HMME at 10μg/ml concentration and the light dose at 2.4~4.8 J/cm2 were selected in the studies. The morphological character 24h post-PDT was investigated by HE Staining. Annexin V and propidium iodide (PI) binding assays were performed to analyze the characteristics of cell death after HMME-PDT. Furthermore, The intracellular distributions of the HMME were measured by the confocal laser scanning microscope. Result It was showed the photocytotoxity to VSMC cells was dose related by Trypan Blue assay. Histology observing suggests HMME-PDT could induce cell death through apoptosis or necrosis, and the apoptosic rate was up to 50.5% by AnnexinV /PI assay. Moreover, the fluorescence images of HMME intracellular localization demonstrated that the HMME diffused into the mitochondria. Conclusion HMME-PDT could significantly inhibite VSMC proliferation and induce apoptosis.

Blue light versus red light for photodynamic therapy of basal cell carcinoma in patients with Gorlin syndrome: A bilaterally controlled comparison study.

PubMed

Maytin, Edward V; Kaw, Urvashi; Ilyas, Muneeb; Mack, Judith A; Hu, Bo

2018-06-01

Photodynamic therapy (PDT) is a non-scarring alternative for treating basal cell carcinoma (BCC) in patients with Basal Cell Nevus Syndrome (BCNS), also known as Gorlin syndrome. In Europe, red light (635 nm) is the predominant source for PDT, whereas in the United States blue light (400 nm) is more widely available. The objective of this study was to conduct a head-to-head comparison of blue light and red light PDT in the same BCNS patients. In a pilot study of three patients with 141 BCC lesions, 5-aminolevulinate (20% solution) was applied to all tumors. After 4 h, half of the tumors were illuminated with blue light and the remainder with red light. To ensure safety while treating this many tumors simultaneously, light doses were escalated gradually. Six treatments were administered in three biweekly sessions over 4 months, with a final evaluation at 6 months. Tumor status was documented with high-resolution photographs. Persistent lesions were biopsied at 6 months. Clearance rates after blue light (98%) were slightly better than after red light (93%), with blue light shown to be statistically non-inferior to red light. Eight suspicious lesions were biopsied, 5 after red light (5/5 were BCC) and 3 after blue light (1 was BCC). Blue light PDT was reportedly less painful. Blue light and red light PDT appear to be equally safe and perhaps equally effective for treating BCC tumors in BCNS patients. Further studies to evaluate long-term clearance after blue light PDT are needed. Copyright © 2018 Elsevier B.V. All rights reserved.

Synergetic effects of 5-aminolevulinic acid and Ascophyllum nodosum seaweed extracts on Asparagus phenolics and stress related genes under saline irrigation.

PubMed

Al-Ghamdi, Abdullah A; Elansary, Hosam O

2018-06-09

Salinity is one of the major agricultural problems that may threat food security and limit the agricultural lands expansion worldwide. Exploring novel tools controlling saline conditions and increase valuable secondary metabolites in the horticultural crops might have outstanding results that serve humanity in the current century. The current study explores the effects of weekly seaweed extracts (7 mL   L -1 ) and/or 5-aminolevulinic acid (3, 5 and 10 ppm) sprays on Asparagus aethiopicus plants subjected to saline stress conditions (2000 and 4000 ppm) for 6 weeks in two consecutive seasons of 2016 and 2017. Under saline conditions, there were stimulatory synergetic effects of seaweed extracts (SWE) and 5-aminolevulinic acid (ALA) on branch length and number of treated plants. Similar increases were also found in fresh and the dry weight of treated plants compared to control. These morphological improvements associated with increased accumulation of specific phenols (robinin, rutin, apigein, chlorogenic acid and caffeic acid) as revealed by High-Performance Liquid Chromatography with Diode-Array Detection (HPLC-DAD). There were increases in the antioxidant activities of leaf extracts, chlorophyll content and sugars and proline accumulation. The transpiration and photosynthetic rates as well as the stomatal conductance were enhanced. The morphological and physiological improvements associated with increased expression of several genes responsible for water management (ANN1, ANN2 and PIP1), secondary metabolite production (P5CS1 and CHS) and antioxidants accumulation (APX1 and GPX3) in plants. Our findings indicate that SWE + ALA had stimulatory synergetic effects on the growth and secondary metabolites of A. aethiopicus subjected to saline conditions. Several mechanisms are involved in such effects including gas exchange control, sugar buildup, increasing non-enzymatic and enzymatic antioxidants control of reactive oxygen species accumulation as well as

Development of a red diode laser system for photodynamic therapy

NASA Astrophysics Data System (ADS)

Halkiotis, Konstantinos N.; Yova, Dido M.; Uzunoglou, Nikolaos K.; Papastergiou, Georgios; Matakias, Sotiris; Koukouvinos, Ilias

1998-07-01

The effectiveness of photodynamic treatment modality has been proven experimentally for a large variety of tumors, during the last years. This therapy utilizes the combined action of light and photosensitizing drug. Until now, a disadvantage of PDT has be the low tissue penetration of light, at the wavelengths of most commonly available lasers, for clinical studies. The red wavelength offers the advantage of increased penetration depth in tissue, in addition several new wavelength offers the advantage of increased penetration depth in tissue, in addition several new photosensitizers present absorption band at the region 630nm to 690nm. The development of high power red diode laser system for photodynamic therapy, has provided a cost effective alternative to existing lasers for use in PDT. This paper will describe the system design, development and performance of a diode laser system, connected with a fiber optic facility, to be used for PDT. The system was based on a high power semiconductor diode laser emitting at 655nm. The laser output power was approximately 60mW at the output of a 62.5/125/900 micron fiber optic probe. FUll technical details and optical performance characteristics of the system will be discussed in this paper.

Effect of photodynamic therapy using benzoporphyrin derivative on the cutaneous immune response

NASA Astrophysics Data System (ADS)

Simkin, Guillermo O.; Obochi, Modestus; Hunt, David W. C.; Chan, Agnes H.; Levy, Julia G.

1995-05-01

In this study, the effect of transdermal photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD) on the development of the immunologically mediated contact hypersensitivity (CHS) response against the hapten dinitrofluorobenzene (DNFB) and on the duration of skin allograft acceptance has been evaluated. In the CHS model it was found that the treatment of hairless strain mice with whole-body transdermal PDT using BPD (1 mg/kg) and LED light (15 J/cm2) resulted in a profound suppression of the CHS reaction if treatment was applied either 48 or 24 hours prior or up to 72 hours after sensitization of abdominal skin with DNFB. Less inhibition of the CHS response was observed if PDT was given one day before the ear challenge with DNFB which was applied 5 days following the initial DNFB sensitization. However, DNFB-exposed, PDT-treated mice retained the capacity to respond maximally to the unrelated contact sensitizer oxazolone. These results are consistent with other models of experimentally induced immune tolerance. allogeneic skin graft studies demonstrated that pretreatment of skin with BPD and light, at levels that did not cause significant tissue damage, significantly enhanced the length of engraftment. Using a separate protocol, photodynamic treatment of recipient mice at various times after transplant had no significant effect on allograft acceptance. Irradiation of skin in the presence of BPD may significantly inhibit the initiation of certain immunological responses within these tissues.

Enhancement of the efficiency of photodynamic therapy by combination with the microtubule inhibitor vincristine

NASA Astrophysics Data System (ADS)

Ma, Li Wei; Berg, Kristian; Danielsen, Havard E.; Iani, Vladimir; Moan, Johan

1996-01-01

Combination effects of photodynamic therapy (PDT) with meso-tetra (di-adjacent- sulfonatophenyl) porphine (TPPS2a) and the microtubule (MT) inhibitor, vincristine (VCR), were studied in the CaD2 mouse tumor model in mice. A synergistic effect was found when VCR, at an almost nontoxic dose (1 mg/kg), was injected i.p. into the mice 6 hr before PDT. The data on mitotic index show a 4 - 5 fold accumulation of the cells in mitosis 6 hr after injection of VCR into the mice. Cell cycle and ploidy distributions in tumor tissues were determined by means of image analysis with measurement of integrated optical density after Feulgen reaction on monolayers. Ploidy distribution of the tumors was not significantly changed 6 and 12 hr after administration of VCR only, while an increasing aneuploidy was observed 24 and 48 hr after VCR treatment. No prominent changes of the cell cycle and ploidy distributions were found in the tumor tissues after PDT or PDT combined with VCR.

Evaluation of antitumor efficiency of experimental interstitial photodynamic therapy on the model of M1 sarcoma.

PubMed

Skugareva, O A; Kaplan, M A; Malygina, A I; Mikhailovskaya, A A

2009-11-01

Antitumor efficiency of interstitial photodynamic therapy was evaluated in experiments on outbred albino rats with implanted M-1 sarcoma. Interstitial photodynamic therapy was carried out using one diffusor at different output power and duration of exposure. The percentage of complete regression of the tumors increased with increasing exposure parameters.

Tyrosine kinase inhibitor induced growth factor receptor upregulation enhances the efficacy of near-infrared targeted photodynamic therapy in esophageal adenocarcinoma cell lines.

PubMed

Hartmans, Elmire; Linssen, Matthijs D; Sikkens, Claire; Levens, Afra; Witjes, Max J H; van Dam, Gooitzen M; Nagengast, Wouter B

2017-05-02

Esophageal carcinoma (EC) is a global health problem, with disappointing 5-year survival rates of only 15-25%. Near-infrared targeted photodynamic therapy (NIR-tPDT) is a novel strategy in which cancer-targeted phototoxicity is able to selectively treat malignant cells. In this in vitro report we demonstrate the applicability of antibody-based NIR-tPDT in esophageal adenocarcinoma (EAC), using the phototoxic compounds cetuximab-IRDye700DX and trastuzumab-IRDye700DX, targeting respectively epidermal growth factor receptor 1 (EGFR) and 2 (HER2). Furthermore, we demonstrate that NIR-tPDT can be made more effective by tyrosine kinase inhibitor (TKI) induced growth receptor upregulation. Together, these results unveil a novel strategy for non-invasive EAC treatment, and by pretreatment-induced receptor upregulation its future clinical application may be optimized.

Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery.

PubMed

Li, Juanjuan; Meng, Xuan; Deng, Jian; Lu, Di; Zhang, Xin; Chen, Yanrui; Zhu, Jundong; Fan, Aiping; Ding, Dan; Kong, Deling; Wang, Zheng; Zhao, Yanjun

2018-05-23

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

Invasion-promoting extracellular matrix composition enhances photodynamic therapy response in 3D pancreatic cancer models

NASA Astrophysics Data System (ADS)

Cramer, Gwendolyn M.; El-Hamidi, Hamid; Celli, Jonathan P.

2017-02-01

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extracellular matrix-rich stromal involvement, but it is not clear how ECM properties that affect invasiveness and chemotherapy response influence efficacy of photodynamic therapy (PDT). To disentangle the mechanical and biochemical effects of ECM composition, we measured the effects of various combinations of ECM proteins on growth behavior, invasive potential, and therapeutic response of multicellular 3D pancreatic tumor models. These spheroids were grown in attachment-free conditions before embedding in combinations of rheologically characterized collagen 1 and Matrigel combinations and treated with oxaliplatin chemotherapy and PDT. We find that cells invading from collagen-embedded tumor spheroids, the least rigid ECM substrate described here, displayed better response to PDT than to oxaliplatin chemotherapy. Overall, our results support that ECM-mediated invading PDAC populations remain responsive to PDT in conditions that induce chemoresistance.

Au Nanoclusters Sensitized Black TiO2-x Nanotubes for Enhanced Photodynamic Therapy Driven by Near-Infrared Light.

PubMed

Yang, Dan; Gulzar, Arif; Yang, Guixin; Gai, Shili; He, Fei; Dai, Yunlu; Zhong, Chongna; Yang, Piaoping

2017-12-01

The low reactive oxygen species production capability and the shallow tissue penetration of excited light (UV) are still two barriers in photodynamic therapy (PDT). Here, Au cluster anchored black anatase TiO 2- x nanotubes (abbreviated as Au 25 /B-TiO 2- x NTs) are synthesized by gaseous reduction of anatase TiO 2 NTs and subsequent deposition of noble metal. The Au 25 /B-TiO 2- x NTs with thickness of about 2 nm exhibit excellent PDT performance. The reduction process increased the density of Ti 3+ on the surface of TiO 2 , which effectively depresses the recombination of electron and hole. Furthermore, after modification of Au 25 nanoclusters, the PDT efficiency is further enhanced owing to the changed electrical distribution in the composite, which forms a shallow potential well on the metal-TiO 2 interface to further hamper the recombination of electron and hole. Especially, the reduction of anatase TiO 2 can expend the light response range (UV) of TiO 2 to the visible and even near infrared (NIR) light region with high tissue penetration depth. When excited by NIR light, the nanoplatform shows markedly improved therapeutic efficacy attributed to the photocatalytic synergistic effect, and promotes separation or restrained recombination of electron and hole, which is verified by experimental results in vitro and in vivo. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Treatment of canine hemangiopericytomas with photodynamic therapy.

PubMed

McCaw, D L; Payne, J T; Pope, E R; West, M K; Tompson, R V; Tate, D

2001-01-01

Canine hemangiopericytomas are a commonly occurring neoplasm with a clinical course of recurrence after surgical removal. This study sought to evaluate Photochlor (HPPH) photodynamic therapy (HPPH-PDT) as an adjuvant therapy to prevent recurrence of tumor after surgical removal. Sixteen dogs with naturally occurring hemangiopericytomas were treated with surgical removal of the tumor followed by PDT using Photochlor as the photosensitizer. Photochlor was injected intravenously at a dose of 0.3 mg/kg. Forty-eight hours later the treatment consisted of surgical removal of the tumor followed by HPPH-PDT. Nine dogs (56%) had recurrence of tumor from 2 to 29 (median 9) months after treatment. These results are comparable or not as good as other forms of therapy. Photochlor photodynamic therapy applied after surgery appears to have no advantage over other forms of therapy in regards to preventing recurrence. Delayed wound healing and infections are problematic and make HPPH-PDT an undesirable addition to surgery for the treatment of this tumor type. Copyright 2001 Wiley-Liss, Inc.

Squamous cell carcinoma of dogs and cats: an ideal test system for human head and neck PDT protocols

NASA Astrophysics Data System (ADS)

Lucroy, Michael D.

2006-02-01

Photodynamic therapy (PDT) is ideally suited for the treatment of head and neck cancer (HNC) in humans. Developing useful PDT protocols for HNC is challenging due to the expense of Phase I and II clinical trials. Moreover, the often-poor predictive value of murine models means that photosensitizers may proceed far into development before problems are noted. Dogs and cats with spontaneous oral squamous cell carcinoma (SCC) share striking similarities with humans affected with oral SCC. These similarities include viral and environmental tobacco smoke as risk factors, location-dependent prognoses, and relative resistance to chemotherapy. The relatively large oral cancers encountered in veterinary patients allow for light and drug dosimetry that are directly applicable to humans. The irregular shape of oral SCC allows a rigorous evaluation of novel photodynamic therapy protocols under field conditions. Because spontaneous tumors in dogs and cats arise in an outbred animal population it is possible to observe an intact host response to PDT. The shorter lifespan of dogs and cats allows rapid accrual of endpoint data. External beam radiation therapy and chemotherapy are commonplace in veterinary medicine, making dogs and cats with spontaneous SCC a useful resource to study the interactions with PDT and other cancer treatment modalities. Our preliminary results demonstrate that PDT is well-tolerated by dogs with oral cancer, and a Phase II clinical trial of zinc-phthalocyanine-based photodynamic therapy is underway in dogs with oral SCC. The usefulness of 5-aminolevulinic acid methyl ester-based PDT is being investigated in cats with oral SCC.

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.

Photodynamic treatment with phenothiazinium photosensitizers kills both ungerminated and germinated microconidia of the pathogenic fungi Fusarium oxysporum, Fusarium moniliforme and Fusarium solani.

PubMed

de Menezes, Henrique Dantas; Tonani, Ludmilla; Bachmann, Luciano; Wainwright, Mark; Braga, Gilberto Úbida Leite; von Zeska Kress, Marcia Regina

2016-11-01

The search for alternatives to control microorganisms is necessary both in clinical and agricultural areas. Antimicrobial photodynamic treatment (APDT) is a promising light-based approach that can be used to control both human and plant pathogenic fungi. In the present study, we evaluated the effects of photodynamic treatment with red light and four phenothiazinium photosensitizers (PS): methylene blue (MB), toluidine blue O (TBO), new methylene blue N (NMBN) and the phenothiazinium derivative S137 on ungerminated and germinated microconidia of Fusarium oxysporum, F. moniliforme, and F. solani. APDT with each PS killed efficiently both the quiescent ungerminated microconidia and metabolically active germinated microconidia of the three Fusarium species. Washing away the unbound PS from the microconidia (both ungerminated and germinated) before red light exposure reduced but did not prevent the effect of APDT. Subcelullar localization of PS in ungerminated and germinated microconidia and the effects of photodynamic treatment on cell membranes were also evaluated in the three Fusarium species. APDT with MB, TBO, NMBN or S137 increased the membrane permeability in microconidia and APDT with NMBN or S137 increased the lipids peroxidation in microconidia of the three Fusarium species. These findings expand the understanding of photodynamic inactivation of filamentous fungi with phenothiazinium PS. Copyright © 2016 Elsevier B.V. All rights reserved.

Photodynamic therapy and the treatment of neoplastic diseases of the larynx

NASA Astrophysics Data System (ADS)

Biel, Merrill A.

1995-05-01

Photodynamic therapy (PDT) is an innovative treatment involving the use of light-sensitive drugs to selectively identify and destroy diseased cells. Therefore, photodynamic therapy has the potential to treat and cure precancerous and early cancerous lesions (carcinoma in situ (CIS), T1 and T2) of the larynx while preserving normal tissue. Twenty-four patients with recurrent leukoplakia and carcinomas of the larynx were treated with PDT with follow-up to 60 months. Fourteen patients with T1 squamous cell carcinomas of the vocal cord, 2 patients with a T2 squamous cell carcinoma of the vocal cord failing radiotherapy, and 6 patients with CIS and sever atypia were treated with PDT and obtained a complete response and are disease free. One patient with a T3 carcinoma of the larynx was treated with PDT but died 5 weeks post-treatment of unrelated causes and could not be assessed. Photodynamic therapy is a promising therapy for treatment of precancerous and cancerous lesions of the larynx. This therapy may be particularly beneficial for the treatment of recurrent carcinomas of the larynx that have failed conventional radiotherapy, thereby preserving voice and eliminating the need for destructive laryngeal surgery.

Inactivation of Vibrio parahaemolyticus by antimicrobial photodynamic technology using methylene blue.

PubMed

Deng, Xi; Tang, Shuze; Wu, Qian; Tian, Juan; Riley, William W; Chen, Zhenqiang

2016-03-30

Vibrio parahaemolyticus is the leading causative pathogen of gastroenteritis often related to contaminated seafood. Photodynamic inactivation has been recently proposed as a strategy for killing cells and viruses. The objective of this study was to verify the bactericidal effects caused by photodynamic inactivation using methylene blue (MB) over V. parahaemolyticus via flow cytometry, agarose gel electrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis. Vibrio parahaemolyticus counts were determined using the most probable number method. A scanning electron microscope and a transmission electron microscope were employed to intuitively analyze internal and external cell structure. Combination of MB and laser treatment significantly inhibited the growth of V. parahaemolyticus. The inactivation rate of V. parahaemolyticus was >99.99% and its counts were reduced by 5 log10 in the presence of 0.05 mg mL(-1) MB when illuminated with visible light (power density 200 mW cm(-2)) for 25 min. All inactivated cells showed morphological changes, leakage of cytoplasm and degradation of protein and DNA. Results from this study indicated that photodynamic technology using MB produced significant inactivation of V. parahaemolyticus mainly brought about by the degradation of protein and DNA. © 2015 Society of Chemical Industry.

Oxygen-dependent delayed fluorescence measured in skin after topical application of 5-aminolevulinic acid.

PubMed

Harms, Floor A; de Boon, Wadim M I; Balestra, Gianmarco M; Bodmer, Sander I A; Johannes, Tanja; Stolker, Robert J; Mik, Egbert G

2011-10-01

Mitochondrial oxygen tension can be measured in vivo by means of oxygen-dependent quenching of delayed fluorescence of protoporphyrin IX (PpIX). Here we demonstrate that delayed fluorescence is readily observed from skin in rat and man after topical application of the PpIX precursor 5-aminolevulinic acid (ALA). Delayed fluorescence lifetimes respond to changes in inspired oxygen fraction and blood supply. The signals contain lifetime distributions and the fitting of rectangular distributions to the data appears more adequate than mono-exponential fitting. The use of topically applied ALA for delayed fluorescence lifetime measurements might pave the way for clinical use of this technique. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vitro investigation of efficient photodynamic therapy using a nonviral vector; hemagglutinating virus of Japan envelope

NASA Astrophysics Data System (ADS)

Sakai, Makoto; Fujimoto, Naohiro; Ishii, Katsunori; Nakamura, Hiroyuki; Kaneda, Yasufumi; Awazu, Kunio

2012-07-01

Photodynamic therapy (PDT) is a photochemical modality approved for cancer treatment. PDT has demonstrated efficacy in early stage lung cancer and esophageal cancer. The accumulation of photosensitizers in cancer cells is necessary to enhance the therapeutic benefits of PDT; however, photosensitizers have low uptake efficiency. To overcome this limitation, a drug delivery system, such as the hemagglutinating virus of Japan envelope (HVJ-E) vector, is required. In this study, the combination of PDT and HVJ-E was investigated for enhancing the efficacy of PDT. The photosensitizers that were evaluated included 5-aminolaevulinic acid (5-ALA), protoporphyrin IX (PPIX), and HVJ-PPIX. The uptake of the photosensitizers as increased twenty-fold with the addition of HVJ-E. The cytotoxicity of conventional 5-ALA was enhanced by the addition of HVJ-E vector. In conclusion, HVJ-E vector improved the uptake of photosensitizers and the PDT effect.

Photodynamic treatment of endodontic polymicrobial infection in vitro

PubMed Central

Fimple, Jacob Lee; Fontana, Carla Raquel; Foschi, Federico; Ruggiero, Karriann; Song, Xiaoqing; Pagonis, Tom C.; Tanner, Anne C. R.; Kent, Ralph; Doukas, Apostolos G.; Stashenko, Philip P.; Soukos, Nikolaos S.

2008-01-01

We investigated the photodynamic effects of methylene blue (MB) on multi-species root canal biofilms comprising Actinomyces israelii, Fusobacterium nucleatum subspecies nucleatum, Porphyromonas gingivalis and Prevotella intermedia in experimentally infected root canals of extracted human teeth in vitro. The four test microorganisms were detected in root canals using DNA probes. Scanning electron microscopy (SEM) showed the presence of biofilms in root canals prior to therapy. Root canal systems were incubated with MB (25 µg/ml) for 10 minutes followed by exposure to red light at 665 nm with an energy fluence of 30 J/cm2. Light was delivered from a diode laser via a 250 µm diameter polymethyl methacrylate optical fiber that uniformly distributed light at 360°. Photodynamic therapy (PDT) achieved up to 80% reduction of colony-forming unit counts. We conclude that PDT can be an effective adjunct to standard endodontic antimicrobial treatment when the PDT parameters are optimized. PMID:18498901

Carbon-1 versus Carbon-3 Linkage of d-Galactose to Porphyrins: Synthesis, Uptake, and Photodynamic Efficiency.

PubMed

Pereira, Patrícia M R; Rizvi, Waqar; Bhupathiraju, N V S Dinesh K; Berisha, Naxhije; Fernandes, Rosa; Tomé, João P C; Drain, Charles Michael

2018-02-21

The use of glycosylated compounds is actively pursued as a therapeutic strategy for cancer due to the overexpression of various types of sugar receptors and transporters on most cancer cells. Conjugation of saccharides to photosensitizers such as porphyrins provides a promising strategy to improve the selectivity and cell uptake of the photosensitizers, enhancing the overall photosensitizing efficacy. Most porphyrin-carbohydrate conjugates are linked via the carbon-1 position of the carbohydrate because this is the most synthetically accessible approach. Previous studies suggest that carbon-1 galactose derivatives show diminished binding since the hydroxyl group in the carbon-1 position of the sugar is a hydrogen bond acceptor in the galectin-1 sugar binding site. We therefore synthesized two isomeric porphyrin-galactose conjugates using click chemistry: one linked via the carbon-1 of the galactose and one linked via carbon-3. Free base and zinc analogs of both conjugates were synthesized. We assessed the uptake and photodynamic therapeutic (PDT) activity of the two conjugates in both monolayer and spheroidal cell cultures of four different cell lines. For both the monolayer and spheroid models, we observe that the uptake of both conjugates is proportional to the protein levels of galectin-1 and the uptake is suppressed after preincubation with an excess of thiogalactose, as measured by fluorescence spectroscopy. Compared to that of the carbon-1 conjugate, the uptake of the carbon-3 conjugate was greater in cell lines containing high expression levels of galectin-1. After photodynamic activation, MTT and lactate dehydrogenase assays demonstrated that the conjugates induce phototoxicity in both monolayers and spheroids of cancer cells.

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.

The application of antimicrobial photodynamic therapy (aPDT) in dentistry: a critical review

PubMed Central

Carrera, E T; Dias, H B; Corbi, S C T; Marcantonio, R A C; Bernardi, A C A; Bagnato, V S; Hamblin, M R; Rastelli, A N S

2017-01-01

In recent years there have been an increasing number of in vitro and in vivo studies that show positive results regarding antimicrobial photodynamic therapy (aPDT) used in dentistry. These include applications in periodontics, endodontics, and mucosal infections caused by bacteria present as biofilms. Antimicrobial photodynamic therapy is a therapy based on the combination of a non-toxic photosensitizer (PS) and appropriate wavelength visible light, which in the presence of oxygen is activated to produce reactive oxygen species (ROS). ROS induce a series of photochemical and biological events that cause irreversible damage leading to the death of microorganisms. Many light-absorbing dyes have been mentioned as potential PS for aPDT and different wavelengths have been tested. However, there is no consensus on a standard protocol yet. Thus, the goal of this review was to summarize the results of research on aPDT in dentistry using the PubMed database focusing on recent studies of the effectiveness aPDT in decreasing microorganisms and microbial biofilms, and also to describe aPDT effects, mechanisms of action and applications. PMID:29151775

The application of antimicrobial photodynamic therapy (aPDT) in dentistry: a critical review

NASA Astrophysics Data System (ADS)

Carrera, E. T.; Dias, H. B.; Corbi, S. C. T.; Marcantonio, R. A. C.; Bernardi, A. C. A.; Bagnato, V. S.; Hamblin, M. R.; Rastelli, A. N. S.

2016-12-01

In recent years there have been an increasing number of in vitro and in vivo studies that show positive results regarding antimicrobial photodynamic therapy (aPDT) used in dentistry. These include applications in periodontics, endodontics, and mucosal infections caused by bacteria present as biofilms. Antimicrobial photodynamic therapy is a therapy based on the combination of a non-toxic photosensitizer (PS) and appropriate wavelength visible light, which in the presence of oxygen is activated to produce reactive oxygen species (ROS). ROS induce a series of photochemical and biological events that cause irreversible damage leading to the death of microorganisms. Many light-absorbing dyes have been mentioned as potential PS for aPDT and different wavelengths have been tested. However, there is no consensus on a standard protocol yet. Thus, the goal of this review was to summarize the results of research on aPDT in dentistry using the PubMed database focusing on recent studies of the effectiveness aPDT in decreasing microorganisms and microbial biofilms, and also to describe aPDT effects, mechanisms of action and applications.

Engineering a Cell-surface Aptamer Circuit for Targeted and Amplified Photodynamic Cancer Therapy

PubMed Central

Han, Da; Zhu, Guizhi; Wu, Cuichen; Zhu, Zhi; Chen, Tao; Zhang, Xiaobing

2013-01-01

Photodynamic therapy (PDT) is one of the most promising and noninvasive methods for clinical treatment of different malignant diseases. Here, we present a novel strategy of designing an aptamer-based DNA nanocircuit capable of the selective recognition of cancer cells, controllable activation of photosensitizer and amplification of photodynamic therapeutic effect. The aptamers can selectively recognize target cancer cells and bind to the specific proteins on cell membranes. Then the overhanging catalyst sequence on aptamer can trigger a toehold-mediated catalytic strand displacement to activate photosensitizer and achieve amplified therapeutic effect. The specific binding-induced activation allows the DNA circuit to distinguish diseased cells from healthy cells, reducing damage to nearby healthy cells. Moreover, the catalytic amplification reaction will only take place close to the target cancer cells, resulting in a high local concentration of singlet oxygen to selectively kill the target cells. The principle employed in this study demonstrated the feasibility of assembling a DNA circuit on cell membranes and could further broaden the utility of DNA circuits for applications in biology, biotechnology, and biomedicine. PMID:23397942

High-b-value diffusion-weighted MR imaging for pretreatment prediction and early monitoring of tumor response to therapy in mice.

PubMed

Roth, Yiftach; Tichler, Thomas; Kostenich, Genady; Ruiz-Cabello, Jesus; Maier, Stephan E; Cohen, Jack S; Orenstein, Arie; Mardor, Yael

2004-09-01

To evaluate the use of diffusion-weighted magnetic resonance (MR) imaging with standard and high b values for pretreatment prediction and early detection of tumor response to various antineoplastic therapies in an animal model. Mice bearing C26 colon carcinoma tumors were treated with doxorubicin (n = 25) and with aminolevulinic acid-based photodynamic therapy (n = 23). Fourteen mice served as controls. Conventional T2-weighted fast spin-echo and diffusion-weighted MR images were acquired once before therapy and at 6, 24, and 48 hours after treatment. Pretreatment and early (1-2 days) posttreatment water diffusion parameters were calculated and compared with later changes in tumor volumes measured on conventional MR images by using the Pearson correlation test. In chemotherapy-treated tumors, a significant correlation (P <.002, r = 0.6) was observed between diffusion parameters that reflected tumor viability, measured prior to treatment, and changes in tumor volumes after therapy. This correlation implies that tumors with high pretreatment viability will respond better to chemotherapy than more necrotic tumors. In tumors treated with photodynamic therapy, no such correlation was found. Changes observed in water diffusion 1-2 days after treatment significantly correlated with later tumor growth rate for both therapies (P <.002, r = 0.54 for photodynamic therapy; P <.0003, r = 0.61 for chemotherapy). High-b-value diffusion-weighted MR imaging has potential use for the early detection of response to therapy and for predicting treatment outcome prior to initiation of chemotherapy. Copyright RSNA, 2004

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.