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Photodynamic therapy is an accepted therapy cancer treatment. Its advantages encourage researchers to delve deeper. The use of nanoparticles in PDT has several advantages including the passive targeting of cancer cells. The aim of this article is to evaluate the effectiveness of AGuIX nanoparticles (activation and guiding of irradiation by X-ray) in the presence or absence of a photosensitizer, Photofrin, under illumination of 630 nm or under X-ray irradiation. The goal is to improve local tumor control by combining PDT with low-dose-X-ray-activated NPs in the treatment of locally advanced metastatic lung cancer. The study of the energy transfer, which occurs after excitation of Gd/Tb chelated in AGuIX in the presence of Photofrin, was carried out. We could observe the formation of singlet oxygen after the light or X-ray excitation of Gd and Tb that was not observed for AGuIX or Photofrin alone, proving that it is possible to realize energy transfer between both compounds. [ABSTRACT FROM AUTHOR]

Photodynamic therapy is an accepted therapy cancer treatment. Its advantages encourage researchers to delve deeper. The use of nanoparticles in PDT has several advantages including the passive targeting of cancer cells. The aim of this article is to evaluate the effectiveness of AGuIX nanoparticles (activation and guiding of irradiation by X-ray) in the presence or absence of a photosensitizer, Photofrin, under illumination of 630 nm or under X-ray irradiation. The goal is to improve local tumor control by combining PDT with low-dose-X-ray-activated NPs in the treatment of locally advanced metastatic lung cancer. The study of the energy transfer, which occurs after excitation of Gd/Tb chelated in AGuIX in the presence of Photofrin, was carried out. We could observe the formation of singlet oxygen after the light or X-ray excitation of Gd and Tb that was not observed for AGuIX or Photofrin alone, proving that it is possible to realize energy transfer between both compounds.

Significance: Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS concentration and light fluence-delivered over time. We introduce an innovative eight-channel PDT dose dosimetry system capable of concurrently measuring light fluence and PS concentration during treatment. Aim: We aim to develop and evaluate an eight-channel PDT dose dosimetry system for simultaneous measurement of light fluence and PS concentration. By addressing uncertainties due to tissue variations, the system enhances accurate PDT dosimetry for improved treatment outcomes. Approach: The study positions eight isotropic detectors strategically within the pleural cavity before PDT. These detectors are linked to bifurcated fibers, distributing signals to both a photodiode and a spectrometer. Calibration techniques are applied to counter tissue-related variations and improve measurement accuracy. The fluorescence signal is normalized using the measured light fluence, compensating for variations in tissue properties. Measurements were taken in 78 sites in the pleural cavities of 20 patients. Results: Observations reveal minimal Photofrin concentration variation during PDT at each site, juxtaposed with significant intra- and inter-patient heterogeneities. Across 78 treated sites in 20 patients, the average Photofrin concentration for all 78 sites is 4.98 µM, with a median concentration of 4.47 µM. The average PDT dose for all 78 sites is 493.17 µMJ/cm², with a median dose of 442.79 µMJ/cm². A significant variation in PDT doses is observed, with a maximum difference of 3.1 times among all sites within one patient and a maximum difference of 9.8 times across all patients. Conclusions: The introduced eight-channel PDT dose dosimetry system serves as a valuable real-time monitoring tool for light fluence and PS concentration during PDT. Its ability to mitigate uncertainties arising from tissue properties enhances dosimetry accuracy, thus optimizing treatment outcomes and bolstering the effectiveness of PDT in cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: We have demonstrated that a fractionated PDT scheme, delivered using a two-hour interval between two light delivery treatments, significantly improves long-term efficacy of Photofrin-mediated PDT while reducing side effects. Reactive Oxygen Species Explicit Dosimetry (ROSED), utilizing direct measurements of in vivo light fluence, in vivo Photofrin concentration, and in vivo tissue oxygenation concentration, were used to determine the concentration of reacted reactive oxygen species, [ROS]rx, as a dosimetry quantity for PDT treatment. We found that a threshold Photofrin dose of 0.78 mM is required for the complete cure (90-day survival) of RIF tumors using fractionated Photofrin-mediated PDT treatment. To our knowledge, this is the first report of this parameter. This study investigates the effect of fractionated (two-part) PDT on the long-term local control rate (LCR) using the concentration of reactive oxygen species ([ROS]rx) as a dosimetry quantity. Groups with different fractionation schemes are examined, including a 2 h interval between light delivery sessions to cumulative fluences of 135, 180, and 225 J/cm2. While the total treatment time remains constant within each group, the division of treatment time between the first and second fractionations are explored to assess the impact on long-term survival at 90 days. In all preclinical studies, Photofrin is intravenously administered to mice at a concentration of 5 mg/kg, with an incubation period between 18 and 24 h before the first light delivery session. Fluence rate is fixed at 75 mW/cm2. Treatment ensues via a collimated laser beam, 1 cm in diameter, emitting light at 630 nm. Dosimetric quantities are assessed for all groups along with long-term (90 days) treatment outcomes. This study demonstrated a significant improvement in long-term survival after fractionated treatment schemes compared to single-fraction treatment, with the optimal 90-day survival increasing to 63%, 86%, and 100% vs. 20%, 25%, and 50%, respectively, for the three cumulative fluences. The threshold [ROS]rx for the optimal scheme of fractionated Photofrin-mediated PDT, set at 0.78 mM, is significantly lower than that for the single-fraction PDT, at 1.08 mM. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is a therapeutic modality that can be used to ablate tumors using the localized generation of reactive oxygen species by combining a photosensitizer, light, and molecular oxygen. This modality holds promise as an adjunctive therapy in the management of colorectal cancer and could be incorporated into neoadjuvant treatment plans under the auspices of prospective clinical trials.Methods: We conducted a search of primary literature published until January 2021, based on PRISMA guidelines. Primary clinical studies of PDT for the management of colorectal cancer were included. Screening, inclusion, quality assessment, and data collection were performed in duplicate. Analyses were descriptive or thematic.Results: Nineteen studies were included, most of which were case series. The total number of patients reported to have received PDT for colorectal cancer was 137, almost all of whom received PDT with palliative intent. The most common photosensitizer was hematoporphyin derivative or Photofrin. The light dose used varied from 32 J/cm2 to 500 J/cm2. Complete tumor response (cure) was reported in 40%, with partial response reported in 43.2%. Symptomatic improvement was reported in 51.9% of patients. In total, 32 complications were reported, the most common of which was a skin photosensitivity reaction.Conclusions: PDT for the management of colorectal cancer has not been well studied, despite promising results in early clinical case series. New, well designed, prospective clinical trials are required to establish and define the role of PDT in the management of colorectal cancer. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a method of treating precancerous diseases and malignant neoplasms. The efficacy of PDT depends on different parameters such as light dosimetry, oxygen availability, and photophysical and physical–chemical properties of the photosensitizer. In PDT, a photosensitizer is activated using light to promote oxygen photosensitization and cellular transport plays a key role in the reach of it to the desired tissue. In particular, to know the effectiveness of the drug delivery in PDT and its dosage forms to target damaged organs, along with such characteristics as water solubility, it is important to know the ability of a substance to penetrate through cell membrane or accumulate in it. Lipophilicity is used to quantify the earlier‐described abilities. We evaluated the lipophilicity of three selected photosensitizers (PS) (protoporphyrin IX, pyropheophorbide‐a and photofrin) by means of three different methods: octanol–water distribution methods (shake‐flask), reversed‐phase high‐performance liquid chromatography (HPLC) and theoretical calculations based on density functional theory (DFT). We describe and compare the results of these various methods. [ABSTRACT FROM AUTHOR]

Porphysomes (PS) are liposome-like nanoparticles comprising pyropheophorbide-conjugated phospholipids that have demonstrated potential as multimodal theranostic agents for applications that include phototherapies, targeted drug delivery and in vivo fluorescence, photoacoustic, magnetic resonance or positron emission imaging. Previous therapeutic applications focused primarily on photothermal therapy (PTT) and suggested that PSs require target-triggered activation for use as photodynamic therapy (PDT) sensitizers. Here, athymic nude mice bearing subcutaneous A549 human lung tumors were randomized into treatment and control groups: PS-PDT at various doses, PS-only and no treatment negative controls, as well as positive controls using the clinical photosensitizer Photofrin. Animals were followed for 30 days post-treatment. PS-PDT at all doses demonstrated a significant tumor ablative effect, with the greatest effect seen with 10 mg/kg PS at a drug-light interval of 24 h. By comparison, negative controls (PS-only, Photofrin-only, and no treatment) showed uncontrolled tumor growth. PDT with Photofrin at 5 mg/kg and PS at 10 mg/kg demonstrated similar tumor growth suppression and complete tumor response rates (15 vs. 25%, p = 0.52). Hence, porphysome nanoparticles are an effective PDT agent and have the additional advantages of multimodal diagnostic and therapeutic applications arising from their intrinsic structure. Porphysomes may also be the first single all-organic agent capable of concurrent PDT and PTT.

Preclinical studies show improved prediction of treatment outcome using [ROS] rx than light fluence rate or PDT dose. We demonstrate ROSED in a clinical setting. Explicit dosimetry of light fluence, photosensitizer concentration, and oxygen concentration is used to quantify the reactive oxygen species explicit dosimetry (ROSED) during Photofrin-mediated pleural PDT. Light fluence and photosensitizer concentration were measured by a customized multi-channel PDT dose dosimeter system. Diffuse correlation spectroscopy (DCS) contact probes were sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (BFI) during intraoperative PDT treatment. Tissue oxygen concentration can be determined by utilizing tumor blood flow measured by DCS. Large inter- and intra-patient heterogeneities in [ROS] rx were observed although an identical light dose of 60 J/cm2 was prescribed to all patients. This study summarizes the current results of ROSED for a Phase II pleural PDT clinical trial. [ABSTRACT FROM AUTHOR]

Multispectral singlet oxygen dosimetry (MSOLD) provides a mean for direct detection of singlet oxygen, responsible for tumor kill for type II PDT. An InGaAs spectrometer or an InGaAs detector coupled with to narrow beam filters (1200, 1240, 1250, 1270, 1300 nm) via 1 mm optical fibers are used to measure singlet oxygen (SO) luminescent spectrum in in-vitro and in-vivo conditions. The spectrum, after fitted to a phosphorescence background a gaussian function for the singlet oxygen peak, is used to determine the singlet oxygen (SO) emission signal. The MSOLD signal is then compared with the singlet oxygen explicit dosimetry (SOED) results, based on direct measurements of light fluence (rate), Photofrin concentration, and tissue oxygenation concentration. MSOLD signal is affected by tissue absorption and scattering and is increasing with increasing Photofrin concentration and light fluence rate. MSOLD is feasible in vitro and in vivo for detecting SO directly. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or pro-survival mechanism in a context-dependent manner. Therefore, we aimed to determine the role of autophagy in Photofrin-based PDT. Methods In vitro cytotoxic/cytostatic effects of PDT were evaluated with crystal violet cell viability assay. Autophagy induction was analyzed by immunoblotting and immunofluorescence using anti-LC3 antibody. Autophagy was inhibited by shRNA-mediated ATG5 knockdown or CRISPR/Cas9-mediated ATG5 knockout. Apoptosis was assessed by flow cytometry analysis of propidium iodide and anexin V-positive cells as well as by detection of cleaved PARP and caspase 3 proteins using immunoblotting. Protein carbonylation was evaluated by the 2,4-dinitrophenylhydrazine (DNPH) method. Results Photofrin-PDT leads to robust autophagy induction in two cancer cell lines, Hela and MCF-7. shRNA-mediated knockdown of ATG5 only partially blocks autophagic response and only marginally affects the sensitivity of Hela and MCF-7 cells to PDT. ATG5 knockout in HeLa cell line utilizing CRISPR/Cas9 genome editing results in increased PDT-mediated cytotoxicity, which is accompanied by an enhanced apoptotic response and increased accumulation of carbonylated proteins. Conclusions Altogether, these observations imply that autophagy contributes to Photofrin-PDT resistance by enabling clearance of carbonylated and other damaged proteins. Therefore, autophagy inhibition may serve as a strategy to improve PDT efficacy.

Significance: Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS concentration and light fluence-delivered over time. We introduce an innovative eight-channel PDT dose dosimetry system capable of concurrently measuring light fluence and PS concentration during treatment., Aim: We aim to develop and evaluate an eight-channel PDT dose dosimetry system for simultaneous measurement of light fluence and PS concentration. By addressing uncertainties due to tissue variations, the system enhances accurate PDT dosimetry for improved treatment outcomes., Approach: The study positions eight isotropic detectors strategically within the pleural cavity before PDT. These detectors are linked to bifurcated fibers, distributing signals to both a photodiode and a spectrometer. Calibration techniques are applied to counter tissue-related variations and improve measurement accuracy. The fluorescence signal is normalized using the measured light fluence, compensating for variations in tissue properties. Measurements were taken in 78 sites in the pleural cavities of 20 patients., Results: Observations reveal minimal Photofrin concentration variation during PDT at each site, juxtaposed with significant intra- and inter-patient heterogeneities. Across 78 treated sites in 20 patients, the average Photofrin concentration for all 78 sites is 4.98    μ M , with a median concentration of 4.47    μ M . The average PDT dose for all 78 sites is 493.17    μ MJ / cm 2 , with a median dose of 442.79    μ MJ / cm 2 . A significant variation in PDT doses is observed, with a maximum difference of 3.1 times among all sites within one patient and a maximum difference of 9.8 times across all patients., Conclusions: The introduced eight-channel PDT dose dosimetry system serves as a valuable real-time monitoring tool for light fluence and PS concentration during PDT. Its ability to mitigate uncertainties arising from tissue properties enhances dosimetry accuracy, thus optimizing treatment outcomes and bolstering the effectiveness of PDT in cancer therapy., (© 2024 The Authors.)

Photofrin/photodynamic therapy (PDT) at sub-lethal doses induced a transient stall in proteasome activity in surviving A549 (p53+/+) and H1299 (p53−/−) cells as indicated by the time-dependent decline/recovery of chymotrypsin-like activity. Indeed, within 3 h of incubation, Photofrin invaded the cytoplasm and localized preferentially within the mitochondria. Its light activation determined a decrease in mitochondrial membrane potential and a reversible arrest in proteasomal activity. A similar result is obtained by treating cells with Antimycin and Rotenone, indicating, as a common denominator of this effect, the ATP decrease. Both inhibitors, however, were more toxic to cells as the recovery of proteasomal activity was incomplete. We evaluated whether combining PDT (which is a treatment for killing tumor cells, per se, and inducing proteasome arrest in the surviving ones) with Bortezomib doses capable of sustaining the stall would protract the arrest with sufficient time to induce apoptosis in remaining cells. The evaluation of the mitochondrial membrane depolarization, residual proteasome and mitochondrial enzymatic activities, colony-forming capabilities, and changes in protein expression profiles in A549 and H1299 cells under a combined therapeutic regimen gave results consistent with our hypothesis.

Background/Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

Though we crossed many milestones in the field of medicine and health care in eradicating some deadly diseases over the past decades, cancer remained a challenge taking the lives of millions of people and having adverse effects on the quality of life of survivors. Chemotherapy and radiotherapy, the two existing major treatment modalities, have severe side effects and patients undergoing these treatments experience unbearable pain. Consequently, clinicians and researchers are working for the alternate treatment regimens, which can provide complete cure with minimum or no side effects. To this end, the present review highlights the major advances and future promises of photodynamic therapy, an emerging and promising therapeutic modality for combating cancer. We delve on various important aspects of photodynamic therapy including principle, mechanism of action, brief history and development of photosensitizers from first generation to the existing third generation, delivery strategies, development or suppression of immunity, combination therapy and future prospects. [ABSTRACT FROM AUTHOR]

Background Iron oxide (Fe 3 O 4 ) nanoparticles (IO-NP) were recently employed in medical applications as a diagnostic tool and drug carrier. Photofrin (PF) is a photosensitizer that clinically is used in Photodynamic therapy (PDT). Study design The photosensitivity of PF and Rose Bengal (RB) mixed with (IO-NP) on red blood cells (RBCs) lysis was investigated. Second, Photohemolysis for post-irradiation (delayed) and during irradiation (continuous) with PF, RB and IO-NP combinations at different concentrations was investigated. Third, the photohemolysis rate, relative lysis steepness and power-concentration dependant parameter were evaluated by modeling and fitting the data using Gompertz function and power law. Methods RBCs were isolated from healthy male human volunteer. Washed cells (7.86 × 10 6 cells/mm 3 ) were incubated with PF only or with IO-NP for 45 min at 37 °C then irradiated to a range of temperatures (4–41 °C). CPH results were recorded and evaluated using Gompertz function. Results The relative steepness of the photohemolysis curves was approximately independent on light dose for delayed irradiation. The presence of IO-NP increases the rupturing time for 50% of the RBCs. Photohemolysis rate for delayed irradiation using the power law, led to 1.7 and 2.3 power dependence, respectively, for PF only and PF mixed with IO-NP. The power dependence of continuous irradiation measurements showed inverse proportionality for different concentrations of IO-NP combined with 2 μg/ml PF concentration and 1.5 μg/ml for RB concentration. Conclusion Photosensitization of RBC with PF or RB mixed with IO-NP inhibited rupturing erythrocyte membrane and therefore a consideration should be taken against their combination in clinical applications. [ABSTRACT FROM AUTHOR]

Accurate photodynamic therapy (PDT) dosimetry is critical for the use of PDT in the treatment of malignant and nonmalignant localized diseases. A singlet oxygen explicit dosimetry (SOED) model has been developed for in vivo purposes. It involves the measurement of the key components in PDT--light fluence (rate), photosensitizer concentration, and ground-state oxygen concentration ([³O2])--to calculate the amount of reacted singlet oxygen ([¹O2]rx), the main cytotoxic component in type II PDT. Experiments were performed in phantoms with the photosensitizer Photofrin and in solution using phosphorescence-based singlet oxygen luminescence dosimetry (SOLD) to validate the SOED model. Oxygen concentration and photosensitizer photobleaching versus time were measured during PDT, along with direct SOLD measurements of singlet oxygen and triplet state lifetime (τΔ and τt), for various photosensitizer concentrations to determine necessary photophysical parameters. SOLD-determined cumulative [¹O2]rx was compared to SOED-calculated [¹O2]rx for various photosensitizer concentrations to show a clear correlation between the two methods. This illustrates that explicit dosimetry can be used when phosphorescence-based dosimetry is not feasible. Using SOED modeling, we have also shown evidence that SOLD-measured [¹O2]rx using a 523 nm pulsed laser can be used to correlate to singlet oxygen generated by a 630 nm laser during a clinical malignant pleural mesothelioma (MPM) PDT protocol by using a conversion formula. [ABSTRACT FROM AUTHOR]

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to evaluate using calculated reacted singlet oxygen concentration ([1O2]rx) to predict Photofrin-PDT outcome in mice bearing radiationinduced fibrosarcoma tumors, as singlet oxygen is the primary cytotoxic species responsible for cell death in type II PDT. Using a combination of fluences (50, 135, 200, and 250 J/cm2) and ϕ (50, 75, and 150 mW/cm2), tumor regrowth rate, k, was determined for each condition. A tumor cure index, CI = 1 - k/kcontrol, was calculated based on the k between PDT-treated groups and that of the control, kcontrol. The measured Photofrin concentration and light dose for each mouse were used to calculate PDT dose and ([1O2]rx), while mean optical properties (μa = 0.9 cm-1, μ's = 8.4 cm-1) were used to calculate ϕ for all mice. CI was correlated to the fluence, PDT dose, and ([1O2]rx) with R2 = 0.35, 0.79, and 0.93, respectively. These results suggest that ([1O2]rx) serves as a better dosimetric quantity for predicting PDT outcome. [ABSTRACT FROM AUTHOR]

Objectives Photodynamic therapy (PDT) is a very effective treatment for superficial malignancies that does not result in loss of normal tissue. Here, we report successful PDT treatment of superficial oral cancers and its clinical outcome with long-term follow up. Materials and methods Thirty-four superficial oral squamous cell carcinomas were treated with PDT, and the effects were evaluated. Each patient received Photofrin (2 mg/kg) intravenously 48 h prior to light irradiation. Photoradiation was performed at doses of 100–150 J/cm 2 using a 630-nm wavelength excimer dye laser. Results Six months after PDT, 30 patients (88.2%) showed complete responses while 9 patients (26.5%) had local relapses during long-term follow-up. The 5-year overall survival, disease-specific survival, and disease-free survival rates were 76.5%, 84.6%, and 63.3%, respectively. Lesions with red patches had a significantly higher recurrence rate than lesions with white patches. Accurate evaluation of the extent of lesions and appropriate photoradiation were important in improving outcomes. Adverse events observed included sunburn and sequestrum formation of alveolar bone. No abnormal laboratory values or systemic complications were observed. Conclusion PDT using Photofrin as the photosensitizer is an effective treatment modality for superficial oral carcinomas, with excellent healing and minimal side effects. [ABSTRACT FROM AUTHOR]

Advanced colorectal cancer has a high mortality rate and conventional treatments have poor therapeutic effects. The aim of the present study was to analyze the recent curative effect and adverse reaction of photofrin photodynamic adjuvant treatment on young patients with advanced colorectal cancer. A total of 23 patients with advanced colorectal cancer who had accepted semiconductor laser photodynamic adjuvant treatment were selected as the observation group. In addition, 30 patients who had accepted concurrent radiotherapy and chemotherapy during the same period served as the control group. The observation group received photofrin (2 mg/kg) intravenously in 100 ml of 5% glucose, followed by the introduction of the endoscopic optical fiber to deliver laser radiation with an intensity of 630 nm wavelength pulse power. After 2 days, necrotic tissues were removed and irradiation of the original or new tumor lesions was performed and necrotic tissues were removed. The total effective rate and survival time was higher and the length of hospital stay was shorter in the observation group in comparison with the control group. The differences were statistically significant (P<0.05). The number of patients in the control and observation groups with symptoms of hematochezia, change in bowel habit, intestinal stimulation and incomplete intestinal obstruction were reduced. Additionally, the reduced ratio of the observation group was significantly increased in comparison with the control group (P<0.05). The adverse reaction rate of the observation group was lower than that of the control group and this difference was also statistically significant (P<0.05). In conclusion, use of photodynamic treatment for young patients with advanced colorectal cancer can effectively improve the clinical symptoms and reduce complications. [ABSTRACT FROM AUTHOR]

• With screening, a large number of early stage and curable lung cancer has been diagnosed. • Surgery and Radiosurgery (SBRT) can be curative for these patients. • Photodynamic therapy (PDT) can also be curative for these patients but is underutilized. • PDT delivered by navigational bronchoscopy is an innovative means to treat these patients. • This case report shows how PDT can be curative for a nonsurgical and non radiosurgical patient. Photodynamic therapy (PDT) is an FDA approved treatment for lung cancer. In the United States the photosensitizer porfimer sodium (Photofrin®, Pinnacle Biologics) is intravenously introduced at 2mg/kg. After approximately 48 h, illumination to activate the photosensitizer is initiated, with 630nm red light at 200J/cm, delivered by fiber-optic catheter, brought to the tumor endo- bronchially, and delivered for 500 s. This will create, in the presence of oxygen, a Type II Photodynamic Reaction (PDR) which generates singlet oxygen species that are tumor ablative. Classically, PDT for lung cancer has been employed for symptomatic central and obstructing tumors with great success. This case report describes an innovative approach to treat a peripheral, early stage lung cancer employing magnetic navigation and endobronchial treatment. We report on a 79 year old male with numerous comorbidities including pulmonary fibrosis, who was found to have a biopsy proven peripheral and solitary non-small cell cancer. Due to prior SBRT (stereotactic body radiation therapy) with dose levels causing radiation fibrosis, he was not a candidate for repeat SBRT, and he was not a surgical candidate due to comorbidities. Tumor control with PDT was achieved without treatment related morbidity. This report details our findings. [ABSTRACT FROM AUTHOR]

Direct detection of singlet-state oxygen ([ 1 O 2 ]) constitutes the holy grail dosimetric method for type II PDT, a goal that can be quantified using multispectral singlet oxygen dosimetry (MSOLD). However, the short lifetime and extremely weak nature of the singlet oxygen signal produced has given rise to a need to improve MSOLD signal-to-noise ratio. This study examines methods for optimizing MSOLD signal acquisition, specifically employing an orthogonal arrangement between detection and PDT treatment light, consisting of two fiber optics - connected to a 632-nm laser and an InGaAs detector respectively. Light collected by the InGaAs detector is then passed through a filter wheel, where spectral emission measurements are taken at 1200 nm, 1240 nm, 1250 nm, 1270 nm, and 1300 nm. The data, after fitting to the fluorescence background and a gaussian-fit for the singlet oxygen peak, is established for the background-subtracted singlet oxygen emission signal. The MSOLD signal is then compared with the singlet oxygen explicit dosimetry (SOED) results, based on direct measurements of in-vivo light fluence (rate), in-vivo Photofrin concentration, and tissue oxygenation concentration. This study focuses on validating the sensitivity and minimum detectability of MSOLD signal in various in-vitro conditions. Finally, the MSOLD device will be tested in Photofrin-mediated PDT for mice bearing Radiation-Induced Fibrosarcoma (RIF) tumors.

Photodynamic therapy (PDT) is an established modality for cancer treatment, and reactive oxygen species explicit dosimetry (ROSED), based on direct measurements of in-vivo light fluence (rate), in-vivo photofrin concentration, and tissue oxygenation concentration, has been proved to provide the best dosimetric quantity which can be used to predict non-fractionated PDT outcome. This study performed ROSED for Photofrin-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. As demonstrated by our previous study, fractionated PDT with a 2-hour time interval can significantly improve the long-term cure rate (from 15% to 65% at 90 days), and it tends to increase as the light dose for the first light fraction gets larger. This study focused on further improving the long-term cure rate without introducing apparent toxicity using combinations of different first light fraction lengths and total light fluences. Photofrin was injected through the mouse tail vein at a concentration of 5 mg/kg. After 18~24 hours, treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Mice were treated using two fractions of light fluences with a 2-hour dark interval. Different dose metrics were quantified, including light fluence, PDT dose, and [ROS]rx. In addition, the total reacted [ROS]rx and treatment outcomes were evaluated and compared to identify the optimal light fraction length and total light fluence.

Photofrin/photodynamic therapy (PDT) at sub-lethal doses induced a transient stall in proteasome activity in surviving A549 (p53+/+) and H1299 (p53-/-) cells as indicated by the time-dependent decline/recovery of chymotrypsin-like activity. Indeed, within 3 h of incubation, Photofrin invaded the cytoplasm and localized preferentially within the mitochondria. Its light activation determined a decrease in mitochondrial membrane potential and a reversible arrest in proteasomal activity. A similar result is obtained by treating cells with Antimycin and Rotenone, indicating, as a common denominator of this effect, the ATP decrease. Both inhibitors, however, were more toxic to cells as the recovery of proteasomal activity was incomplete. We evaluated whether combining PDT (which is a treatment for killing tumor cells, per se, and inducing proteasome arrest in the surviving ones) with Bortezomib doses capable of sustaining the stall would protract the arrest with sufficient time to induce apoptosis in remaining cells. The evaluation of the mitochondrial membrane depolarization, residual proteasome and mitochondrial enzymatic activities, colony-forming capabilities, and changes in protein expression profiles in A549 and H1299 cells under a combined therapeutic regimen gave results consistent with our hypothesis. [ABSTRACT FROM AUTHOR]

Despite initially positive responses, recurrences after Photodynamic treatment (PDT) can occur and there is need for improvement in the effectiveness of PDT. Our study uniquely showed that there was a significantly gap junctional intercellular communication (GJIC)-dependent PDT cytotoxicity. The presence of GJIC composed of Connexin 32 increased the PDT phototoxicity in transfected HeLa cells and in the xenograft tumors, and the enhanced phototoxicity of Photofrin-mediated PDT by GJIC was related with ROS and calcium pathways. Our study indicates the possibility that up-regulation or maintenance of gap junction functionality may be used to increase the efficacy of PDT. [ABSTRACT FROM AUTHOR]

Background/Aims: 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. Methods: 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. Results: 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. Conclusion: 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 [ABSTRACT FROM AUTHOR]

BACKGROUND: Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS: Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm2 administered continuously over 24 h (10-2 dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ⩽33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS: Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm2 and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm2. None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm2 over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS: The MTD of CLIPT was established at 50 J/cm2 administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention. [ABSTRACT FROM AUTHOR]

• PDT is successful for lung cancer treatment. • PDT is generally used in central lesions. • This report features PDT for peripheral lung cancer. Photodynamic therapy (PDT) is an internationally approved ablation technique for endo-bronchial lung cancer. The majority of reported outcomes are for central and obstructing lesions where excellent long term control is possible. With the current trend of screening high risk for lung cancer populations, a larger cohort of patients are now diagnosed with earlier stage disease. When these early tumors are located in the lung periphery the current therapeutic options include surgery or radiation therapy. Still, many patients may not be candidates or amenable for these procedures. As PDT is a well tolerated non-thermal outpatient therapy to treat lung cancer and as newer bronchoscopy techniques allow for treatment of peripheral lesions, PDT may be an option. We report a case of a primary non-small cell lung cancer treated by interstitial PDT through placement of the diffusing fiber via magnetic navigational bronchoscopy. Forty eight hours post 2 mg/kg intravenous (IV) injection of Photofrin®, a single 500 second illumination of 200 J/cm at 630 nm was directed to the solitary peripheral lesion without complication. On day 30, as a part of planned therapy, lobectomy was undertaken. Pathology reported necrosis and no viable remaining tumor. At 90 days follow up, the patient remains well,with no evidence of disease. Additional details follow in the report. [ABSTRACT FROM AUTHOR]

• Microfluidic device performs single parallel test for different light irradiations. • Eight different intensities are generated from a single light-emitting diode. • Eight different color dye concentrations function as light intensity filters. • Optimum light intensities and photosensitizer doses were determined for cell lines. • High-throughput microfluidic system analyzes effects of light intensity during PDT. : Photodynamic therapy utilizes light energy with a photosensitizer (a light-sensitive drug) to kill cancer cells through creation of singlet oxygen via light activation. When a photosensitizer is injected into the bloodstream and exposed to a specific wavelength of light, it generates oxygen to destroy or damage nearby cancer cells, while minimizing side effects on normal cells. Although photodynamic therapy is effective for treating cancer, various parameters, such as the optimum light intensity and photosensitizer dose, are currently poorly understood due to the complexity of conventional experimental schemes. : To effectively perform a simultaneous single parallel test for several different light irradiation conditions on each cell, a microfluidic device was developed to generate eight different intensities from a single light-emitting diode source, through eight different color dye concentrations functioning as light intensity filters. To show that this novel high-throughput microfluidic system can analyze the effects of various light intensities during photodynamic therapy, the optimum light intensities and photosensitizer doses were determined for two different cancer cell lines. : Optimum light intensities and photosensitizer were determined for all cell lines. The photodynamic therapy effects in response to different irradiated light intensities were characterized by analyzing cell viability after photosensitizer treatment : The developed platform is capable of being used as a photodynamic therapy screening tool. The proposed platform provides a simple and robust way to optimize the combined parameters of light intensity and dosage for diverse types of cancer cells. [ABSTRACT FROM AUTHOR]

The authors investigated the efficacy of photodynamic therapy against infantile hemangioma using a hemangioma animal model. Eighty-three hemangioma specimens from five children were implanted into nude mice. The gross and volume changes of the implants were evaluated for up to 13 weeks. The histological change of the implant was evaluated at 5 weeks after transplantation. Photodynamic therapy was performed between 6 and 10 weeks after transplantation. The photosensitizer uptake of the implant was evaluated at 24 h after photosensitizer administration. The implant response was evaluated at 0, 12, and 24 h after light delivery. The change in ATF3 levels, a transcription factor induced under severe hypoxic conditions, was investigated immediately after treatment. The implant volume increased slowly during the first 4 weeks and then involuted. At 5 weeks after transplantation, plump endothelial cells formed tightly packed sinusoidal channels, and the endothelial cells were positive for CD31 and GLUT1 expression. At 24 h after photosensitizer administration, confocal analysis showed that the photosensitizer was present within CD31-positive cells. The implant volume was significantly decreased in the treated implants compared with the untreated implants ( p < 0.0001). At 24 h after light delivery, most cells had collapsed. ATF3 expression increased gradually and then reached a maximum level at 4 h after treatment. Photodynamic therapy was effective in the treatment of infantile hemangioma. Apoptosis, a major mechanism of hemangioma destruction in the early phase, might be caused by ischemic injury as well as direct effects of photodynamic therapy. [ABSTRACT FROM AUTHOR]

Summary: Objective: To investigate the effectiveness and side effects of photofrin-photodynamic therapy (PDT) for intractable bronchial lung cancer. Methods: Thirty patients were classified as stage II–IV intractable bronchial lung cancer with lumen obstruction after they failed previous treatment regimens such as surgery, radiotherapy and chemotherapy. PDT was performed with 630nm laser light (Diomed) delivered through cylinder diffusing tip quartz fibers that was passed through the biopsy channel of a flexible endoscope 48h after intravenous injection of the photosensitizer photofrin (2mg/kg body weight). 72h after the first irradiation, the endoscopic procedure was repeated, necrotic tissues were mechanically removed and the deep original lesions and newly exposed cancer lesions were re-treated, and, if necessary, the areas were cleaned repeatedly. Results: The total response rate CR+PR was 86.7%, and the mean percentage of obstruction due to tumors at different treated sites decreased from 90% to 16.7% at discharge after PDT. The KPS score was significantly improved after PDT. Conclusions: PDT of intractable bronchial lung cancer effectively reduces the amount of lumen obstruction, and improves the patient's quality of life. It may be an effective palliative treatment with minor side effects on patients with advanced bronchial lung cancer. [Copyright &y& Elsevier]

Photodynamic therapy (PDT) is a method of treating precancerous diseases and malignant neoplasms. The efficacy of PDT depends on different parameters such as light dosimetry, oxygen availability, and photophysical and physical-chemical properties of the photosensitizer. In PDT, a photosensitizer is activated using light to promote oxygen photosensitization and cellular transport plays a key role in the reach of it to the desired tissue. In particular, to know the effectiveness of the drug delivery in PDT and its dosage forms to target damaged organs, along with such characteristics as water solubility, it is important to know the ability of a substance to penetrate through cell membrane or accumulate in it. Lipophilicity is used to quantify the earlier-described abilities. We evaluated the lipophilicity of three selected photosensitizers (PS) (protoporphyrin IX, pyropheophorbide-a and photofrin) by means of three different methods: octanol-water distribution methods (shake-flask), reversed-phase high-performance liquid chromatography (HPLC) and theoretical calculations based on density functional theory (DFT). We describe and compare the results of these various methods., (© 2022 John Wiley & Sons Ltd.)

• The highest extrusion bond strength was shown by group 1 canal disinfected with Riboflavin and 17% EDTA at all three levels. • The lowest extrusion bond strength was displayed in group 5 canal cleaned with 2.25% NaOCl and 17% EDTA (control). • Intragroup assessment disclosed a decrease in EBS from cervical one-third to apical one-third in all experimental groups. To assess the influence of different photosensitizers activated by PDT as a disinfectant in comparison to conventional sodium hypochlorite (NaOCl) on the EBS (extrusion bond strength) of FRCP with radicular dentin. A total of fifty single-rooted human maxillary central incisors with fully developed apices were selected. Endodontic treatment of samples was performed using 10 K file to obtain patency than sequentially with a 25 K file followed by rotary pro tapers till F2 with constant irrigation. The canal was dried and obturated with corresponding gutta-percha and sealer. A Peso reamer was employed to prepare post space. Based on canal disinfection regimes, samples were divided into five groups. Group 1 Riboflavin (RF)+17%EDTA, group 2 Rose bengal (RB) +17%EDTA, group 3 Curcumin CP +17%EDTA, group 4 Porfimer sodium, Photofrin (PS) +17%EDTA and group 5 2.25% NaOCl +17% EDTA (control). Following disinfection, the canal space of all specimens was dried followed by FRCP cementation. Specimens were placed on a Universal testing machine (UTM) for EBS. The type of bond failure was evaluated using a stereomicroscope. ANOVA and Tukey multiple comparison tests were used to compare means. The highest EBS was shown by group 1 canal disinfected with riboflavin (RF) and 17% EDTA at all three levels. The lowest EBS was displayed in group 5 canal cleaned with 2.25% NaOCl and 17% EDTA. Intragroup assessment disclosed a decrease in EBS from cervical one-third to apical one-third in all experimental groups. Intergroup comparison revealed group 4 using PS and 17% EDTA and group 5 canal disinfected with 2.25% NaOCl and 17% EDTA at all three levels of root structure coronal, middle, and apical exhibited comparable EBS (p >0.05). Root canal dentin treated with different PS (RF, RB, CP) has the potential to be used as canal disinfection as it demonstrates better EBS than the conventional disinfecting regime (2.25% NaOCl +17% EDTA). PS and 17% EDTA as a canal disinfectant need further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The influence of electroporation on the Photofrin uptake and distribution was evaluated in the breast adenocarcinoma cells (MCF-7) and normal Chinese hamster ovary cells (CHO) lacking voltage-dependent channels in vitro. Photofrin was used at a concentration of 5 and 25 μM. The uptake of Photofrin was assessed using flow cytometry and fluorescence microscopy methods. Cells viability was evaluated with crystal violet assay. Our results indicated that electropermeabilization of cells, in the presence of Photofrin, increased the uptake of the photosensitizer. Even at the lowest electric field intensity (700 V/cm) Photofrin transport was enhanced. Flow cytometry results for MCF-7 cells revealed ~1.7 times stronger fluorescence emission intensity for cells exposed to Photofrin and electric field of 700 V/cm than cells treated with Photofrin alone. Photofrin was effective only when irradiated with blue light. Our studies on combination of photodynamic reaction with electroporation suggested improved effectiveness of the treatment and showed intracellular distribution of Photofrin. This approach may be attractive for cancer treatment as enhanced cellular uptake of Photofrin in MCF-7 cells can help to reduce effective dose of the photosensitizer and exposure time in this type of cancer, diminishing side effects of the therapy. [ABSTRACT FROM AUTHOR]

Summary: Background and objective: Pancreatic cancer is a leading cause of cancer-related deaths in men and women. Early clinical studies suggest that photodynamic therapy (PDT) might be a useful modality in the management of this deadly disease. In this study, the photocytotoxicity of Photofrin-mediated PDT on different human pancreatic cancer cells (BxPc-3, HPAF-II, Mia PaCa-2, MPanc-96, PANC-1 and PL-45) was examined. Materials and methods: After co-incubating cancer cells with Photofrin (0–10μg/ml) for 4h, the cells were irradiated with 0–6J/cm2 of 630nm light. The effect of Photofrin PDT on the survival of cells were examined using tetrazolium-based colorimetric assay and clonogenic assay. PDT-induced apoptosis was analyzed by flow cytometry. Expressions of apoptosis-related proteins were determined by western blot analysis. Results: Photofrin PDT strongly inhibited the survival of pancreatic cancer cells. A small portion of cells (<15%) underwent apoptosis 24h after PDT at LD50. Cleavage of caspase-3, caspase-8, caspase-9 and PARP after PDT were also confirmed. BxPc-3, Mia PaCa-2, MPanc-96, and PANC-1 cells were more sensitive and HPAF-II and PL-45 cells less sensitive. Conclusion: Photofrin PDT can induce apoptosis and inhibit survival of human pancreatic cancer cells. [Copyright &y& Elsevier]

Summary: Background: Photodynamic therapy (PDT) is a minimally invasive treatment modality for early and superficial malignancy or premalignancy in the head and neck regions. However, few studies have examined the use of Photofrin-mediated PDT to manage early carcinoma and dysplasia in the oral cavity. Methods: Between January 2004 and November 2008, 25 T1 to T2 patients with N0 oral squamous cell carcinoma and mucosal dysplasia in the oral cavity were treated by Porfimer sodium (Photofrin®)-mediated PDT at Nagasaki University Hospital. Clinical responses were evaluated according to the guidelines of the Response Evaluation Criteria in Solid Tumors (RECIST). After the PDT and a 2-year follow-up period, disease specific survival rates were then calculated. Results: A total of 30 regions in 25 patients (18 with squamous cell carcinoma and 7 with epithelial dysplasia with hyperkeratosis in the oral cavity) were treated by PDT. Complete response was achieved in 24 of the 25 patients (96%), with a partial response found in the remaining patient. For the three patients who exhibited recurrence at 4, 5, and 15 months after PDT, salvage surgery or a second PDT was performed. Of these three patients, one died due to another disease, while one died due to local lymphatic metastasis that occurred during the follow-up period. Overall, the disease specific survival rate was 95.8%. Treatment-related edema and pain emerged within 24h after irradiation. Pain control using non-steroid anti-inflammatory drugs and opiates was required for 3–4 weeks in all patients. Complete healing was attained at 4–6 weeks after the treatment. No persistent problems related to functional or esthetic outcomes were noted. [Copyright &y& Elsevier]

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett's oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ = 5.39, p = 0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p < 0.05). The rate of buried glands with either drug was significantly higher post-PDT (48 % of patients) than pre-PDT (20 %). ALA-PDT has a better risk profile than Photofrin-PDT. In patients with BE length ≤6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BE, neither PDT drug is sufficiently efficacious to warrant routine use. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been demonstrated to be an effective minimally invasive treatment modality for early esophageal cancer. However, the molecular action in esophageal cancer during PDT is hardly known. EGFR has been known to downregulate in various cancer cells during PDT. In this study, we investigated the effects of Photofrin-mediated PDT on cell death and expression of EGFR in CE48T/VGH (CE48T) esophageal squamous cell carcinoma cells. We found that the photosensitizer Photofrin in the absence of light exposure can downregulate the expression of EGFR at both transcription and translation levels. Higher concentrations of Photofrin results in cytotoxicity whereas lower doses of Photofrin inhibit EGFR expression under dark control without inducing significant cell death. This Photofrin-associated inhibition of EGFR was repeated in lung cancer, cervical cancer, and glioblastoma cells. Another esophageal squamous cell carcinoma cell line CE81T/VGH (CE81T) was found to be resistant to Photofrin-induced inhibition of EGFR as well as to Photofrin-mediated dark toxicity compared with CE48T. The resistance to the cytotoxicity in CE81T cells became insignificant when the Photofrin-treated cells were further irradiated by red light (Photofrin-PDT). We suggest Photofrin modulates the expression of EGFR in cancer cells. However, efficient cell death still requires the combination of Photofrin and light irradiation in esophageal squamous cell carcinoma cells. [ABSTRACT FROM AUTHOR]

Abstract: We aimed to investigate the role of the ABCG2 transporter in the efficacy of sonodynamic therapy (SDT) with Photofrin in the glioma stem-like cells (GSCs) isolated and cultured from U251 glioma cells. Immunocytochemistry and flow cytometry analyses showed that ABCG2 was overexpressed in GSCs, and the percentage of ABCG2-positive GSCs was approximately 100%. The effect of ABCG2 on Photofrin extrusion in the absence or presence of a specific inhibitor of ABCG2 (fumitremorgin C; FTC) was investigated by determining the intracellular concentration of Photofrin in GSCs incubated with 20μg/ml Photofrin. Extrusion of Photofrin by ABCG2 was inhibited by 10μM FTC, which significantly increased the intracellular Photofrin concentration (p <0.05) from 0.32±0.11μg/106 cells to 0.89±0.13μg/106 cells. MTT and TUNEL assays showed that the antitumor effect of SDT (incubation of GSCs with 20μg/ml Photofrin for 6h in the dark and ultrasonic activation at 1.0MHz and 0.5W/cm2 for 2min) was significantly improved by FTC pretreatment (p <0.05). Moreover, incubation of GSCs with FTC significantly increased the relative production of ROS in response to SDT. The overexpression of ABCG2 in GSCs results in efflux of Photofrin, indicating that the antitumor effect of SDT with Photofrin may be reduced in GSCs overexpressing ABCG2. However, since FTC improves the efficacy of SDT in GSCs by inhibiting ABCG2-mediated efflux of Photofrin, FTC may be useful in SDT treatment of ABCG2-expressing cancer cells. [Copyright &y& Elsevier]

Photofrin-mediated photodynamic therapy (PF-PDT) can induce cell apoptosis via the mitochondria/caspase-3 pathway. Here, we further investigate the mechanism involved in the mitochondrial apoptotic process induced by PF-PDT. A high-level intracellular reactive oxygen species (ROS) generation in mitochondria, mitochondrial swelling, and dissipation of mitochondrial transmembrane potential were observed immediately after irradiation, indicating that mitochondria were the major ROS generation sites and also the first oxidative damage sites after PF-PDT treatment. For mitochondrial permeability detection, the decrease of calcein fluorescence emission intensity and release of cytochrome c were observed immediately after PF-PDT treatment, indicating the occurrence of mitochondrial inner membrane permeabilization (MIMP) and the mitochondrial outer membrane permeabilization (MOMP). However, cytochrome c release was not prevented by cyclosporine (CsA), a specific inhibitor of mitochondrial permeability transition (MPT). Taken together, these results demonstrated that PF-PDT caused simultaneous onset of MIMP and MOMP immediately after the treatment, and MOMP was independent of the MPT. Besides, inducible mitochondrial ROS generation played key roles in PF-PDT-induced cell apoptosis. This study will be benefit for understanding the mechanism involved in the initial mitochondrial oxidative damage by PF-PDT. [ABSTRACT FROM AUTHOR]

Summary: Objective: To compare the short-term curative effect of photodynamic therapy (PDT), PDT combined with chemotherapy and chemotherapy alone on the advanced esophageal cancer patients. Methods: Retrospective analysis of 90 patients of esophageal cancer underwent PDT, PDT combined with chemotherapy and chemotherapy alone from 2004 to 2007 (stages III–IV), including 27 cases received PDT alone, 33 cases received PDT combined with chemotherapy and 30 cases chemotherapy alone. The enrolled patients were treated with intravenous administration of Photofrin as the photosensitizer at a dose of 2mg/kg. 630nm laser irradiation was performed through optical fiber that passed through the biopsy channel of a flexible endoscope after 48h. Two days later, the necrotic tissue was removed, and the primary sites and other newly identified lesions were subjected to a second irradiation and then the residual necrotic tissue was removed according to the patients’ condition. Electronic endoscopy was performed to observe the effectiveness on tumor after 1 month. In PDT combined with chemotherapy group, chemotherapy regimen was 5-FU and DDP, administered 4 cycles after PDT and chemotherapy alone group only chemotherapy regimen 5-FU and DDP for four cycles. All the 90 patients were followed up for 2 years. Results: Symptomatic palliation rate of the PDT alone group, the complex treatment group and chemotherapy alone group was 85.2%, 93.9% and 60.0%, respectively, and effective rate under endoscopy was 85.2%, 90.9% and 63.3%, respectively, there is no statistically significant difference; the survival rate of 2 years was 29.6%, 54.5% and 16.7%, respectively, and medium survival time is longer (III stages 13m, 22m, 10m; IV stages 7m, 5m, 4m), there is statistically significant difference (p =0.046). Conclusion: PDT combined with chemotherapy for the advanced esophageal cancer is superior to PDT alone and chemotherapy alone. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is a promising adjuvant therapy in cancer treatment. However, cancers resistant to PDT, mediated through the efflux of photosensitisers by means of P-glycoprotein or ATP-binding cassette transporter proteins, have been reported. The DNA repair has also been suggested to be responsible for PDT resistance, but little is known about the repair pathways and mechanisms involved. Therefore, this study aimed to investigate the possible function of six major DNA repair mechanisms in glioma cells resistant to Photofrin-mediated PDT (Ph-PDT).Methods: The U87 glioma cells relatively resistant to Ph-PDT were obtained by recovering the viable cells 3 h after PDT treatment. The mRNA and protein expression levels of DNA repair genes were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and western blotting, respectively. Small-interfering RNA and chromatin-immunoprecipitation assays were used to further examine the relationship between AlkB, an alkylation repair homologue 2 (Escherichia coli) (ALKBH2) and Ph-PDT responsiveness, and transcription factors involved in ALKBH2 transcription.Results: The ALKBH2 of DNA damage reversal was significantly increased at both mRNA and protein levels from 30 min to 48 h post-treatment with Ph-PDT. Conversely, down-regulating ALKBH2 expression enhances Ph-PDT efficiency. Furthermore, our data clearly show for the first time that tumour protein (TP53) is directly involved by binding to the promoter of ALKBH2 in mediating Ph-PDT resistance.Conclusion: C The DNA damage reversal mechanisms may have important functions in Ph-PDT resistance through the activation of ALKBH2 by TP53. [ABSTRACT FROM AUTHOR]

A theoretical study on the static linear (α) and nonlinear (β and γ) optical properties in gas phase of Photofrin and Foscan molecules is reported. These compounds are known as porphyrin derivatives which act as photosensibilizers in photo dynamic therapy for cancer treatment. The geometric parameters of Photofrin and Foscan were fully optimized using ab initio and Density Functional Theory levels, at Hartree-Fock and B3LYP hybrid functional approach, respectively. The STO-3G, 3-21G* and the 3-21+G standard basis sets were employed for the calculations. The 3-21+G basis set is augmented with one s and three p diffuse functions for carbon, nitrogen, oxygen and sodium atoms. The bond distances and the bond angles of the two optimized molecules obtained with different method/basis set combinations show only minor variation. The Hartree-Fock and B3LYP methods provide a suitable evaluation of the geometrical and optical properties of Photofrin and Foscan molecules, since the calculated α _{ave}, β _{v} and γ _{ave} results are in good agreement with previous reports for similar porphyrin derivatives. The optical properties of Foscan and Photofrin molecules have the same tendencies: the α _{ave} results have an almost linear relationship with the conjugated bond number, the β _{v} results are mainly determined by the nature and symmetry of the susbstituent groups to the porphyrin centre and the γ _{ave} results are extremely depending on the calculation strategies. [ABSTRACT FROM AUTHOR]

Background/purpose: Photodynamic therapy (PDT) is a non-invasive cancer therapy that has a strong antitumor effect with intravenous administration of Photofrin. However, Photofrin causes light hypersensitivity that impairs the quality of life (QOL) of patients, and thus an improved method of administration is needed. Here, we report the antitumor effect of local administration of Photofrin in combination with a vasodilator, lidocaine hydrochloride. Method: The antitumor effect was investigated in nude mice transplanted with HeLa cells. An incision was made near the tumor and Photofrin dissolved in lidocaine jelly was applied directly to the tumor. The tumor was irradiated at 100 J/cm2 with a yttrium aluminum garnet (YAG)-dye laser (630 nm) at 2 h after the direct application and the tumor volume was measured for 30 days after PDT to investigate the antitumor effect. In some mice, the tumor was excised 24 h after PDT and the depth of necrosis was measured in the excised specimen. Result: The tumor was mostly necrotized by PDT following direct application of 10 mg/ml Photofrin dissolved in lidocaine jelly and the effect was greater than with direct application of Photofrin alone. The increase in tumor volume observed in control mice was significantly inhibited in mice that received PDT after direct application of Photofrin in lidocaine jelly. Conclusion: PDT using direct application of Photofrin in lidocaine jelly has a strong antitumor effect in mice and this approach may avoid the adverse effects of systemic Photofrin administration. [ABSTRACT FROM AUTHOR]

Our objective was to examine the effect of time intervals between Photofrin injection and laser irradiation [i.e., drug-light interval (DLI)] on the mode of action of Photofrin photodynamic therapy (PDT). Kunming mice transplanted with sarcoma-180 cells were used as an animal model. The tumor-bearing mice in the control group were given neither photosensitizer nor laser irradiation. PDT groups were given intravenous (i.v.) injection of Photofrin (7.5 mg/kg) prior to being irradiated with a 630 nm laser at 120 J/cm(2) at different DLIs (1 min-48 h). Tumors and overlying skin were visually examined daily. Histopathological and electron microscopic examinations were carried out 48 h after PDT. Survival rates were recorded. The mice in the groups that had experienced short DLIs (<60 min) showed stronger skin reactions than the groups subjected to long DLIs (>6 h). Histological examination showed that antitumor effects were achieved mainly by the destruction of tumor blood vessels and the formation of thrombosis at short DLIs, whereas, at long DLIs, the tumor cells were killed directly by PDT-mediated cytotoxicity. Electron microscopy revealed various degrees of mitochondrial swelling. The survival rate of the mice subjected to long DLIs was slightly higher than that of the mice subjected to short DLIs. Both vascular (e.g., tumor vessel destruction) and cellular (e.g., cytotoxicity) effects contributed to Photofrin PDT-induced tumor ablation. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been proven effective for treatment of several types of cancer. Photodynamic therapy alone, however, attains limited cures with some tumours and there is need for its improved efficacy in such cases. Sphingolipid (SL) analogues can promote tumour response in combination with anticancer drugs. In this study, we used mouse SCCVII squamous cell carcinoma tumours to determine the impact of Photofrin-PDT on the in vivo SL profile and the effect of LCL29, a C6-pyridinium ceramide, on PDT tumour response. Following PDT, the levels of dihydroceramides (DHceramides), in particular C20-DHceramide, were elevated in tumours. Similarly, increases in DHceramides, in addition to C20:1-ceramide, were found in PDT-treated SCCVII cells. These findings indicate the importance of the de novo ceramide pathway in Photofrin-PDT response not only in cells but also in vivo. Notably, co-exposure of SCCVII tumours to Photofrin-PDT and LCL29 led to enhanced tumour response compared with PDT alone. Thus, we show for the first time that Photofrin-PDT has a distinct signature effect on the SL profile in vitro and in vivo, and that the combined treatment advances PDT therapeutic gain, implying translational significance of the combination. [ABSTRACT FROM AUTHOR]

Summary: Photodiagnosis (PD) for cutaneous malignancy attempts to differentiate between normal and diseased skin without the need for histological evaluation. This technique exploits natural or induced differences in fluorescent signatures between these tissues. The technique may be as simple as using ultraviolet light in combination with clinical exam to as complex as optical tomography. While the need is great due to the enormous number of skin lesions currently requiring physical biopsy, the results so far generated are not as specific or sensitive as is required in the clinic. This brief review outlines the value of PD, its potential applications and shortcomings as well as a short primer on the most common technique employed in clinical practice. [Copyright &y& Elsevier]

Angiosarcoma, a malignant tumor of vascular endothelial cell origin, is a lethal disease for which complete cure is rarely seen. The objective of this study was to determine the efficiency of photodynamic therapy (PDT) as a new treatment for angiosarcoma. PDT (630 nm, 25 J/cm2) using Photofrin for a mouse angiosarcoma cell line of human origin (ISOS-1) showed that the rate of cell death increased with increase in the concentration of a photosensitizer (LD50: ∼2 μg/ml). Furthermore, PDT (630 nm, 100 J/cm2) with Photofrin (5 mg/kg, i.v.) in mice transplanted with ISOS-1 cells resulted in complete disappearance of the tumor in 40% of mice and marked inhibition of tumor growth in the remaining 60%. Significant increases in TUNEL-positive cells and Ki-67-positive cells ware seen 4 h after PDT, indicating that PDT led to not only cell death but also inhibition of the proliferation of angiosarcoma cells. The results show that PDT is effective for treatment of angiosarcoma. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an effective treatment option for various types of invasive tumors. The efficacy of PDT treatment depends strongly on selective cell uptake and selective excitation of the tumor. The characterization of fluorescence lifetimes of photosensitizers localized inside living cells may provide the basis for further investigation of in vivo PDT dosage measurements using time-domain spectroscopy and imaging. In this communication, we investigated the fluorescence lifetime of localized Photofrin and delta-aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX) in living MAT-LyLu (MLL) rat prostate adenocarcinoma cells. The MLL cells were incubated with the photosensitizers, and then treated with light under well-oxygenated conditions using a two-photon fluorescence lifetime imaging microscope (FLIM). Fluorescence lifetime images of these cells were recorded with average lifetimes of 5.5 plusmn 1.2 ns for Photofrin and 6.3 plusmn 1.2 ns for ALA-induced PpIX. When localized in cells, the lifetimes of both photosensitizers were found to be significantly shorter than those measured in organic solutions. The result for PpIX is consistent with literature values, while the lifetime of Photofrin is shorter than what has been reported. These results suggest that time-domain methods measuring photosensitizer lifetime changes may be good candidates for in vivo PDT dosage monitoring. [ABSTRACT FROM PUBLISHER]