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Using a rat model of type 1 diabetes (T1D) obtained by treatment with streptozotocin, an antibiotic that destroys pancreatic β-cells, we evaluated the influence of subsequent hyperglycemia on the morphology and physiology of the Harderian gland (HG). HG is located in the medial corner of the orbit of many terrestrial vertebrates and, in rodents, is characterized by the presence of porphyrins, which being involved in the phototransduction, through photo-oxidation, produce reactive oxygen species activating the autophagy pathway. The study focused on the expression of some morphological markers involved in cell junction formation (occludin, connexin-43, and α-tubulin) and mast cell number (MCN), as well as autophagic and apoptotic pathways. The expression of enzymes involved in steroidogenesis [steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase (3β-HSD)] and the level of lipid peroxidation by thiobarbituric acid reactive species assay were also evaluated. The results strongly indicate, for the first time, that T1D has a negative impact on the pathophysiology of rat HG, as evidenced by increased oxidative stress, morphological and biochemical alterations, hyperproduction and secretion of porphyrins, increased MCN, reduced protein levels of StAR and 3β-HSD, and, finally, induced autophagy and apoptosis. All the combined data support the use of the rat HG as a suitable experimental model to elucidate the molecular damage/survival pathways elicited by stress conditions., (© 2023 Wiley Periodicals LLC.)

Aims: To retrospectively compare the therapeutic effect of modified double-dose photodynamic therapy (PDT) with standard-dose PDT in patients with circumscribed choroidal haemangioma (CCH)., Methods: Thirty-nine patients with CCH were categorised in two groups by PDT type. The standard-dose group (n=12) was treated with 6 mg/m 2 verteporfin and a 689 nm laser for 83 s. The modified double-dose group (n=27) received one vial of verteporfin (15 mg), and the dose was calculated for each patient based on body surface area, then irradiance time was adjusted according to calculated verteporfin dose to achieve a 'double'-dose effect. Treatment outcomes (foveal centre thickness, subretinal fluid, tumour thickness and diameter) were measured at baseline and 1 year post-treatment; subretinal fluid levels were also measured at 1, 3 and 6 months post-treatment., Results: No differences in baseline characteristics were found between the two groups. The modified double-dose group showed a greater reduction in tumour thickness (45.3% vs 20.6%, p=0.013) and tumour volume (60.0% vs 30.0%, p=0.006) at 1 year post-treatment. Recurred or non-complete resolution patients in the standard-dose group tended to show much increased subretinal fluid than those in the modified double-dose group at 1-year post-treatment., Conclusion: Modified double-dose PDT is an effective and safe protocol for symptomatic CCH management, greater tumour regression and potentially better resolution of subretinal fluid compared with standard PDT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

In the present work, two photosensitizing drugs, Temoporfin and Verteporfin have been studied. Both have regular approval in Europe, Temoporfin for the treatment of head and neck cancers and Verteporfin for the treatment of age-related macular degeneration (AMD). The treatment modality, known as "Photodynamic Therapy" (PDT), involves drug activation with visible light in the presence of oxygen and production of reactive oxygen species (ROS) to destroy the pathological tissues. Both drugs are inactive in the absence of light, presenting only few side effects. The incorporation of the two drugs into a SOPC bilayer -used as a model membrane- was studied by ATR-FTIR. An original approach was applied, involving lyotropic transitions and a very slow dehydration rate of the sample. In low water content and dry film, Temoporfin highly affects stretching vibrations of SOPC chains and polar groups, showing that Temoporfin is inserted into the bilayer in both apolar and polar regions. In fully hydrated layers, Temoporfin - SOPC interactions still take place but only impact Temoporfin vibration bands. Verteporfin shows smaller effect on both chain and polar groups' vibrations of SOPC, with the exception of choline group, suggesting that Verteporfin is inserted into the bilayer to a lesser extent and remains at the bilayer polar interface. These results can be used to better understand drugs behavior in biological media., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To compare the efficacy and safety of subthreshold micropulse laser treatment (SML), standard-fluence photodynamic therapy (PDT) and low-fluence PDT in patients with chronic central serous chorioretinopathy (cCSC)., Methods: This retrospective study included 52 eyes of 46 patients with chronic CSC who were treated with 577nm SML (n=23), standard-fluence PDT (verteporfin 6mg/m 2 and light energy 50J/cm 2 ) (n=13), or low-fluence PDT (verteporfin 6mg/m 2 and light energy 25J/cm 2 ) (n=16). The mean changes in best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) parameters, including central retinal thickness (CRT), subretinal fluid (SRF) height, and ellipsoid zone (EZ) disruption, over the follow-up period were evaluated., Results: The mean follow-up period was 8.42±3.34 months. In the SML group, the SRF resolution time was longer than the other groups. At 1 month, the SML group's mean CRT was higher than the other groups. The BCVA improvement was statistically significant in all groups (P<0.05), but in the SML group, it was slower than the other groups. Three eyes in the low-fluence and one eye in the standard-fluence PDT group received a second PDT treatment. The mean number of SML treatments was 2.48±1.08. If the EZ was intact, the rate of complete resolution of SRF was higher than if the EZ was disrupted or lost., Conclusion: SML, standard-fluence PDT, and low-fluence PDT can all improve visual acuity in cCSC. Standard-fluence and low-fluence PDT induced a more rapid reabsorption of the fluid, improvement of BCVA, and equal safety compared with SML. More treatment sessions of SML were required than with the other treatment modalities., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Antibiotics are commonly used to control, treat, or prevent bacterial infections, however bacterial resistance to all known classes of traditional antibiotics has greatly increased in the past years especially in hospitals rendering certain therapies ineffective. To limit this emerging public health problem, there is a need to develop non-incursive, non-toxic, and new antimicrobial techniques that act more effectively and quicker than the current antibiotics. One of these effective techniques is antibacterial photodynamic therapy (aPDT). This review focuses on the application of porphyrins in the photo-inactivation of bacteria. Mechanisms of bacterial resistance and some of the current 'greener' methods of synthesis of meso-phenyl porphyrins are discussed. In addition, significance and limitations of aPDT are also discussed. Furthermore, we also elaborate on the current clinical applications and the future perspectives and directions of this non-antibiotic therapeutic strategy in combating infectious diseases.

The development of imaging-guided smart drug delivery systems for combinational photodynamic/chemotherapy of the tumor has become highly demanded in oncology. Herein, redox-responsive theranostic polymeric nanoparticles (NPs) were fabricated innovatively using low molecular weight heparin (LWMH) as the backbone. Chlorin e6 (Ce6) and alpha-tocopherol succinate (TOS) were conjugated to LMWH via cystamine as the redox-sensitive linker, forming amphiphilic Ce6-LMWH-TOS (CHT) polymer, which could self-assemble into NPs in water and encapsulate paclitaxel (PTX) inside the inner core (PTX/CHT NPs). The enhanced near-infrared (NIR) fluorescence intensity and reactive oxygen species (ROS) generation of Ce6 were observed in a reductive environment, suggesting the cystamine-switched "ON/OFF" of Ce6. Also, the in vitro release of PTX exhibited a redox-triggered profile. MCF-7 cells showed a dramatically higher uptake of Ce6 delivered by CHT NPs compared with free Ce6. The improved therapeutic effect of PTX/CHT NPs compared with mono-photodynamic or mono-chemotherapy was observed in vitro via MTT and apoptosis assays. Also, the PTX/CHT NPs exhibited a significantly better in anti-tumor efficiency upon NIR irradiation according to the results of in vivo combination therapy conducted on 4T1-tumor-bearing mice. The in vivo NIR fluorescence capacity of CHT NPs was also evaluated in tumor-bearing nude mice, implying that the CHT NPs could enhance the accumulation and retention of Ce6 in tumor foci compared with free Ce6. Interestingly, the anti-metastasis activity of CHT NPs was observed against MCF-7 cells by a wound healing assay, which was comparable to LMWH, suggesting LMWH was promising for construction of nanocarriers for cancer management.

Purpose: To assess the short-term outcome of and possible temporary vision loss after half-dose verteporfin photodynamic therapy (PDT) in patients with chronic central serous chorioretinopathy (cCSC)., Methods: In this prospective study, 14 eyes of 13 cCSC patients who underwent half-dose PDT were included. Patients received spectral-domain optical coherence tomography (OCT) imaging and microperimetry before PDT on the day of treatment and 1 week after treatment., Results: Five patients (38%) reported worsening of visual complaints in the week after half-dose PDT. No significant changes in both central foveal thickness, height of subretinal fluid, and choroidal thickness on optical coherence tomography imaging and retinal sensitivity on microperimetry were observed, neither in the patients who did not experience worsening of visual symptoms, nor in those who did., Conclusion: Worsening of visual complaints can occur in a noteworthy number of cCSC patients in the first week after half-dose verteporfin PDT. Despite the fact that no significant short-term changes on both optical coherence tomography and microperimetry have been detected in this study, the assessment could be of importance for the long-term outcome of treatment and needs further investigation.

Objective: To assess the effect of photodynamic therapy (PDT) with talaporfin sodium, a second-generation photosensitizer, on oral squamous cell carcinoma (SCC)., Methods: Eight patients who were diagnosed with oral SCC without any metastasis and underwent talaporfin sodium-mediated PDT (t-PDT) were included in this study. Biopsies were performed 4-6 weeks after t-PDT. The clinical response was evaluated using Response Evaluation Criteria in Solid Tumors., Results: Complete response (CR) was achieved in six of eight cases, and two cases showed partial response (PR) as a clinical outcome of t-PDT. Recurrence occurred in one of the CR cases 9 months after irradiation. The patient underwent tumor resection and no recurrence was found after surgery. The two cases with PR died from the cancer despite additional PDT., Conclusion: t-PDT is an effective treatment strategy for oral SCC. Talaporfin sodium has an advantage with regard to early elimination from the body compared with porfimer sodium., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The present study was performed to establish and characterize new human osteosarcoma cell lines resistant to pyropheophorbide-α methyl ester‑mediated photodynamic therapy (MPPa-PDT). MPPa-PDT-resistant cells are isolated from the human osteosarcoma MG63 and HOS cell lines and two resistant populations were finally acquired, including MG63/PDT and HOS/PDT. Cell Counting Kit-8 (CCK-8) assay was used to determine the MPPa-PDT, cisplatin (CDDP) resistance and proliferation of MG63, MG63/PDT, HOS and HOS/PDT cells. The intracellular ROS were analyzed using DCFH-DA staining. The colony formation, invasion and migration of parental and resistant cells were compared. FCM was employed to examine the cell cycle distribution, the apoptosis rate and the proportion of CD133+ cells. The fluorescence intensity of intracellular MPPa was observed by fluorescence microscopy and quantified using microplate reader. The protein levels were assessed by western blotting (WB). Compared with two parental cells, MG63/PDT and HOS/PDT were 1.67- and 1.61-fold resistant to MPPa-PDT, respectively, and also exhibited the resistance to CDDP. FCM assays confirmed that both MG63/PDT and HOS/PDT cells treated with MPPa-PDT displayed a significantly lower apoptosis rate in comparison with their corresponding parental cells. The expression of apoptosis-related proteins (i.e. cleaved-caspase 3 and cleaved‑PARP), intracellular ROS and the antioxidant proteins (HO-1 and SOD1) in MG63/PDT and HOS/PDT cells was also lower than that in parental cells. Both MG63/PDT and HOS/PDT cells exhibited changes in proliferation, photosensitizer absorption, colony formation, invasion, migration and the cell cycle distribution as compared to MG63 and HOS cells, respectively. Compared to MG63 and HOS cells, both resistant cell lines had a higher expression of CD133, survivin, Bcl-xL, Bcl-2, MRP1, MDR1 and ABCG2, but a lower expression of Bax. The present study successfully established two resistant human osteosarcoma cell lines which are valuable to explore the resistance-related mechanisms and the approaches to overcome resistance.

Purpose: To evaluate the incidence, outcomes, and risk factors for hemorrhagic complications in eyes with polypoidal choroidal vasculopathy (PCV) following photodynamic therapy (PDT)., Methods: Medical records of 94 eyes of 86 consecutive patients with PCV who underwent PDT between January 2007 and December 2014 were retrospectively reviewed. The diagnosis of PCV was based on clinical features and indocyanine green angiography. Eyes were treated with PDT monotherapy or a combination of PDT plus anti-vascular endothelial growth factor. PDT was performed at (standard [SFPDT] or reduced fluence RFPDT)., Results: Ninety-four eyes had 119 PDT treatment sessions (mean: 1.3 sessions). Mean presenting vision was 0.46 ± 0.44 logarithm of the minimum angle of resolution (logMAR). Following PDT, ten eyes (11%) of nine patients had hemorrhagic complications such as subretinal hemorrhage (SRH; n = 5), subretinal pigment epithelium (RPE) hemorrhage (n = 1), breakthrough vitreous hemorrhage (BVH; n = 3), and SRH with sub-RPE hemorrhage and BVH (n = 1). Median interval to hemorrhage following PDT was 2 months. Age (P = 0.842), duration of symptoms (P = 0.352), number of laser spots (P = 0.219), and laser spot size (LSS) (P = 0.096) were not significantly associated with increased risk of hemorrhagic complications. Female gender was associated with reduced risk of hemorrhage (P = 0.045). SFPDT was significantly associated with increased risk of hemorrhage (P = 0.026). The probability of developing hemorrhagic complications in SFPDT group was 0.24 compared to 0.07 in RFPDT group (P = 0.039). Multivariate logistic regression analysis showed SFPDT as the only significant risk factor for hemorrhage following PDT (odds ratio 5.3, 95% confidence interval 1.1-24.8, P = 0.03). Mean final vision was 0.61 ± 0.53 logMAR at mean follow-up of 33 months (median = 22 months; range = 2-157 months)., Conclusion: Age, LSS, number of laser spots, preexisting hemorrhages, or use of anticoagulants were not associated with increased risk of hemorrhagic complications. SFPDT was significantly associated with increased risk of hemorrhagic complications in such eyes.

Photodynamic therapy (PDT) is a promising antineoplastic modality in the oncology field. We assessed the safety of repeated intravenous administrations of sinoporphyrin, a porphyrin derivative, with and without illumination in rats. Toxicokinetic studies of single and multiple administrations of sinoporphyrin were also carried out. Sprague-Dawley rats were randomly assigned to the dark-toxicity and PDT groups. Animals in the dark toxicity group received an i.v. infusion of sinoporphyrin at 3 doses: 2 mg kg -1 , 6 mg kg -1 , and 18 mg kg -1 . The PDT group included 2 doses of sinoporphyrin (2 mg kg -1 and 18 mg kg -1 ), and the rats received 60 J of 630 nm laser illumination 24 h after photosensitizer infusion. The treatments were repeated every 7 days for 5 cycles and were followed by a 14-day recovery period. Systematic analyses were conducted at the end of treatment and recovery periods. Blood samples were obtained 5 min, 30 min, 2 h, 8 h, 24 h, 48 h, 72 h, and 96 h after the first and fifth treatments for toxicokinetic studies. Sinoporphyrin-PDT led to the death of one out of 270 rats; the dead animal had been treated with 18 mg kg -1 sinoporphyrin and died at the end of the fifth PDT treatment. Liver injury, the primary toxicity observed in the study, was identified using biochemical tests, necropsy, and histopathology. Elevated white blood cell and neutrophil counts were found in the rats in both the dark toxicity and PDT groups. Skin lesions at the illumination site were obvious in the PDT group. Pigment deposits were detected in multiple organs such as the liver, spleen, lymph nodes, and ovaries in the 6 mg kg -1 and 18 mg kg -1 groups. No other abnormalities were observed. The toxicokinetic parameters of single and multiple sinoporphyrin administrations were calculated and compared. Repeated sinoporphyrin administrations both alone and in combination with laser illumination were tolerable, and all toxicities were transient. The no observed adverse effect level (NOAEL) for repeated sinoporphyrin administration and sinoporphyrin-PDT was 6 mg kg -1 and 2 mg kg -1 , respectively. Further studies are warranted.

The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7-/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection., Competing Interests: The authors have declared that no competing interests exist.

Association of choroidal neovascular (CNV) membrane with circumscribed choroidal hemangioma is rare, and the CNV development after photodynamic therapy (PDT) is also rare. Etiopathogenesis of these associations is poorly understood. We noted the development of CNV over choroidal hemangioma after PDT therapy in a young female patient in our hospital. Temporal association of CNV development after PDT treatment points toward the possible side effects of PDT. Repeat injections of antivascular endothelial growth factor (ranibizumab) regressed the CNV resulting in a favorable visual outcome.

Purpose: To compare the efficacy of half-dose vs half-time photodynamic therapy (PDT) guided by fluorescein angiography (FA) for the treatment of central serous chorioretinopathy (CSC)., Design: Two-center, retrospective, comparative case series., Methods: Sixty-one eyes with acute or chronic CSC involving fovea were recruited; 35 eyes received half-dose PDT and 26 eyes received half-time PDT. Improvement in best-corrected visual acuity (BCVA), resolution of subretinal fluid (SRF) demonstrated by optical coherence tomography (OCT), and recurrence of CSC after PDT were compared between the 2 groups., Results: The mean follow-up time after PDT was 14.8 ± 13.3 months. Both groups showed significant improvement in BCVA at months 1, 3, 6, and 12 after PDT (P < .05 for all times). Multiple regression analysis showed that PDT type was not correlated with visual improvement (P > .05 for all times). All eyes that received half-time PDT showed complete resolution of SRF within 6 months after PDT, but 3 eyes that received half-dose PDT had persistent SRF before loss to follow-up at months 5, 7, and 8 (P = .21 between 2 groups). Three of 32 eyes in the half-dose group and 2 of 26 eyes in the half-time group had recurrence of CSC during follow-up; all recurrent cases had complete SRF resolution after another PDT treatment. No adverse systemic or ocular side effects were observed in any cases., Conclusions: Half-dose and half-time FA-guided PDT were both effective and safe in treating CSC and showed similar efficacy in visual improvement and SRF resolution., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vascular targeted photodynamic therapy (VTP), with use of verteporfin as a photosensitizer is one of the few therapies, which has been shown to effectively slow the progression of the "wet" form of age-related macular degeneration (AMD), and even to stabilize visual acuity over many years. Although, due to considerable advance of AMD treatment, it is currently not recommended in monotherapy of AMD, however, its combination with steroids and anti-angiogenic biologic drugs may reveal high therapeutic potential in the treatment of neovascular AMD. The future of VTP as a method of AMD treatment is development of new selective and targeted photosensitizer and combination of this method with other therapeutic strategies targeting cellular structures or pathways involved in AMD progression., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancers and diseases. Photosensitizers are critical components for PDT. Sinoporphyrin sodium, referred to as DVDMS, is a newly identified photosensitizer that was isolated from Photofrin. Here, we evaluated the effects of DVDMS-mediated PDT (DVDMS-PDT) on tumor cell proliferation and metastasis in the highly metastatic 4T1 cell line and a mouse xenograft model. DVDMS-PDT elicited a potent phototoxic effect in vitro, which was abolished using the reactive oxygen species (ROS) scavenger N-acetylcysteine. In addition, DVDMS-PDT effectively inhibited the migration of 4T1 cells in scratch wound-healing and transwell assays. Using an in vivo mouse model, DVDMS-PDT greatly prolonged the survival time of tumor-bearing mice and inhibited tumor growth and lung metastasis, consistent with in vitro findings. PDT with DVDMS had a greater anti-tumor efficacy than clinically used Photofrin. Moreover, preliminary toxicological results indicate that DVDMS is relatively safe. These results suggest that DVDMS is a promising sensitizer that warrants further development for use in cancer treatment with PDT or other sensitizing agent-based therapies.

Importance: A randomized clinical trial is needed to evaluate what is the best photodynamic therapy (PDT) protocol to use for acute central serous chorioretinopathy., Objective: To compare the efficacy and safety of a 50% dose of verteporfin (a method of PDT) with the efficacy and safety of a 30% dose for acute central serous chorioretinopathy., Design, Setting, and Participants: A multicenter, noninferiority, double-masked, randomized, controlled, clinical trial in which 131 patients (131 eyes) with acute central serous chorioretinopathy for less than 6 months were recruited with a follow-up of 12 months from university-based ophthalmology practices., Interventions: Patients were randomly assigned to either a 50% dose of verteporfin (the 50%-dose PDT group) or a 30% dose (the 30%-dose PDT group)., Main Outcomes and Measures: The 2 primary outcome measures were the proportion of eyes with complete absorption of subretinal fluid and the proportion of eyes with complete disappearance of fluorescein leakage at 6 and 12 months. The secondary outcome measures included the subretinal fluid recurrent rate, the fluorescein leakage recurrent rate at 12 months, the mean best-corrected visual acuity, the retinal thickness of the foveal center, and the maximum retinal thickness at each scheduled visit., Results: The noninferiority of the 30%-dose PDT compared with the 50%-dose PDT for the primary outcomes was not demonstrated. The optical coherence tomography-based improvement rate in the 30%-dose PDT group was less than that in the 50%-dose PDT group both at 6 months (73.8% vs 92.9%; α = 0.0125, P = .006) and at 12 months (75.4% vs 94.6%; α = 0.0125, P = .004). The fluorescein angiography-based improvement rate in the 30%-dose PDT group was less than that in the 50%-dose PDT group both at 6 months (68.9% vs 91.1%; α = 0.0125, P = .003) and at 12 months (68.9% vs 92.9%; α = 0.0125, P = .001). The subretinal fluid recurrence rate in the 30%-dose PDT group was greater than that in the 50%-dose PDT group (24.0% vs 5.7% at 12 months; P = .010, determined by use of the log-rank test). The fluorescein leakage recurrent rate in the 30%-dose PDT group was significantly higher than that in the 50%-dose PDT group (16.7% vs 3.8% at 12 months; P = .03, determined by use of the log-rank test). No ocular adverse event was encountered in the study., Conclusions and Relevance: A 50% dose of verteporfin may be more effective at resolving subretinal fluid and fluorescein leakage, and with better visual outcomes, than a 30% dose for acute central serous chorioretinopathy., Trial Registration: clinicaltrials.gov Identifier: NCT01574430.

Purpose: To compare the chorioretinal tissue response after different half-strength parameters of photodynamic therapy (PDT) in rabbits., Methods: The study included 4 groups, and each group contained 4 animals. The full dose served as the control group: verteporfin (4 mg/kg) with 600 mW/cm(2) irradiance from a diode laser at 689 nm applied to the retina for 8 s. One parameter was changed to half-strength in the other 3 groups. The HLaser group received half-strength laser irradiance. The HTime group was exposed to photosensitization for half the time, and the HDose group received half the drug dose. Six laser spots were generated in each of the eyes of every rabbit and documented graphically. The lesions were examined on days 1, 7, and 42 after PDT treatment using color fundus imaging, fluorescein angiography (FA), and histopathology analysis., Results: PDT treatment in rabbits caused chorioretinal damage in all 4 groups. FA on day 1 showed that the use of half the laser irradiance, half the drug dose, or half the photosensitizing time tended to decrease the damage to the chorioretinal tissue in terms of the number of occlusions and the area of occlusion, but only the results from half the laser irradiance were significantly different. In addition, the HLaser and HDose groups showed significantly less apoptosis by TUNEL staining on day 1., Conclusions: Among these PDT parameters, decreasing the laser irradiance by half showed the greatest decrease in chorioretinal damage in an experimental animal model.

Photodynamic therapy (PDT) is a common treatment on retinal capillary hemangioma. We applied PDT to a patient with von Hippel-Lindau(VHL) syndrome and she developed severe massive exudative retinal detachment the next day, which is a rare complication for PDT. After intraocular anti-VEGF agent and peribulbar dexamethasone several times to the patient, her subretinal fluid disappeared and hemangiomas atrophied. Treatment with Anti-VEGF agent and corticosteroid is effective for such complication., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To assess the visual and anatomic outcomes of central serous chorioretinopathy (CSC) after verteporfin photodynamic therapy (PDT)., Design: Retrospective case series., Participants: Patients with CSC who underwent PDT., Methods: Members of the Macula Society were surveyed to retrospectively collect data on PDT treatment for CSC. Patient demographic information, PDT treatment parameters, fluorescein angiographic information, optical coherence tomography (OCT) metrics, pre- and post-treatment visual acuity (VA), and adverse outcomes were collected online using standardized forms., Main Outcome Measures: Visual acuities over time and presence or absence of subretinal fluid (SRF)., Results: Data were submitted on 265 eyes of 237 patients with CSC with a mean age of 52 (standard deviation [± 11]) years; 61 were women (26%). Mean baseline logarithm of the minimum angle of resolution (logMAR) VA was 0.39±0.36 (20/50). Baseline VAs were ≥20/32 in 115 eyes (43%), 20/40 to 20/80 in 97 eyes (37%), and ≤20/100 in 47 eyes (18%). Normal fluence was used for PDT treatment in 130 treatments (49%), half-fluence was used in 128 treatments (48%), and very low fluence or missing information was used in 7 treatments (3%). The number of PDT treatments was 1 in 89%, 2 in 7%, and 3 in 3% of eyes. Post-PDT follow-up ranged from 1 month to more than 1 year. Post-PDT VA was correlated with baseline VA (r = 0.70, P < 0.001). Visual acuity improved ≥3 lines in <1%, 29%, and 48% of eyes with baseline VA ≥20/32, 20/40 to 20/80, and ≤20/100, respectively. Subretinal fluid resolved in 81% by the last post-PDT visit. There was no difference in the response to PDT when analyzed by age, race, fluence setting, fluorescein angiography (FA) leakage type, corticosteroid exposure, or fluid location (subretinal or pigment epithelial detachment; all P > 0.01). Complications were rare: Retinal pigment epithelial atrophy was seen in 4% of patients, and acute severe visual decrease was seen in 1.5% of patients., Conclusions: Photodynamic therapy was associated with improved VA and resolution of SRF. Adverse side effects were rare., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the efficacy and safety of half-fluence vs half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (CSC)., Design: Multicenter retrospective comparison study., Methods: Retrospective review of 56 patients affected by chronic CSC, including 28 patients (31 eyes) who received half-fluence PDT and 28 patients (29 eyes) who received half-dose PDT. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), and resolution of subretinal fluid on optical coherence tomography at 1 and 12 months were assessed., Results: The mean logMAR BCVA improved significantly (P < .001), both in the half-fluence group (from 0.187 [± 0.187] to 0.083 [± 0.164]) and in the half-dose group (from 0.126 [± 0.091] to 0.068 [± 0.091]), at 12 months, without significant difference between the 2 groups. At 1 month a complete resolution of subretinal fluid was observed in 19 half-fluence-treated eyes (61.3%) and in 25 half-dose-treated eyes (86.2%) (P = .04). At 12 months, a complete resolution of subretinal fluid was achieved in 26 half-fluence-treated eyes (83.9%) and 29 half-dose-treated eyes (100%) (P = .0529). Nine eyes (29%) in the half-fluence group and 5 eyes (17.2%) in the half-dose group had at least 1 recurrence of subretinal fluid during the follow-up. Overall there were 15 and 5 recurrences in the half-fluence PDT and half-dose PDT groups, respectively (P = .07). In no eye of either groups was atrophy of the retinal pigment epithelium observed in the area of treatment., Conclusion: Half-dose PDT induced a more rapid reabsorption of the fluid, a more lasting effect, and equal safety with respect to half-fluence PDT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Intravenous (i.v.) formulations with various amounts of organic solvents [PEG400 , propylene glycol (PG), cremophor EL (CrEL)] were used to deliver a fluorinated sulfonamide bacteriochlorin to mice, rats, and minipigs. Biodistribution studies in mice showed that a low-content CrEL formulation combines high bioavailability with high tumor-to-muscle and tumor-to-skin ratios. This formulation was also the most successful in the photodynamic therapy of mice with subcutaneously implanted CT26 murine colon adenocarcinoma tumors. Pharmacokinetic studies in mice and minipigs revealed that with the same low CrEL formulation, the half-life of the photosensitizer in the central compartment was longer in minipigs. Differences in biodistribution with the various formulations, and in pharmacokinetics between the two animal species with the same formulation, are attributed to the interaction of the formulations with low-density lipoproteins (LDLs). Skin photosensitivity studies in rats showed that 30 min exposure of the skin to a solar simulator 7 days after i.v. administration of the fluorinated sulfonamide bacteriochlorin at 1 mg kg(-1) did not elicit significant skin reactions., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a case with retinal arteriole occlusion after a single photodynamic therapy (PDT). A 33-year-old man presented with decreased visual acuity of the right eye, 20/200, for four months. Diagnosed as circumscribed choroidal haemangioma (CCH), he was treated with the PDT. Specifically, 6 mg/m(2) of verteporfin was administered intravenously in 10 min. Laser treatment was performed 15 min after the infusion with an exposure of 75 J/cm(2) for 125 s. The patient was followed up a week later and then every month for 5 months. Complaining about central visual field defect two days post treatment, he was diagnosed with inferior macular artery occlusion with FA. After three months further treatment, the tumor regressed completely but local retinal atrophy was observed. The best corrected visual acuity (BCVA) was 20/30 with visual field defect. Following this, extensive blood tests were performed, revealing no abnormality. Our result indicates that under certain conditions infarction of retinal arterioles can develop following PDT., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A 60-year-old man had a combination of laser in situ keratomileusis and Kamra corneal inlay implantation to correct presbyopia. Although the outcome was favorable postoperatively, central serous chorioretinopathy was observed in the left eye along with a decrease in the uncorrected (UDVA) and corrected (CDVA) distance visual acuities and the corrected near visual acuity (CNVA). Photodynamic therapy (PDT) was later performed in a university hospital. After PDT, the patient experienced a decline in the visual acuity and came to our clinic a month after the PDT. Degeneration and a scar were observed at the location of the inlay due to the heat and burning. Flattening of the corneal topography was also observed where the corneal scar was located, along with a significant decrease in CDVA in the left eye. Prior to any surgery in which the corneal inlay is an impediment, surgeons should take advantage of the reversibility of the Kamra inlay by explanting the inlay., (Copyright © 2013 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy., Methods: In this multicenter, double-masked, primarily indocyanine green angiography-guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3-5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography-assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety., Results: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination., Conclusion: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months.

Purpose: To evaluate the effect of photodynamic therapy on amelanotic choroidal melanoma., Methods: Nine patients with posteriorly located amelanotic choroidal melanomas, one with a pigmented portion, underwent photodynamic therapy using verteporfin as the photosensitizing agent. The basal diameters ranged from 4 mm to 16 mm and the heights from 1.3 mm to 5.7 mm. Treatment was repeated until the melanoma was completely flat or its height had reached a stable end point. Tumor response was assessed by clinical examination, photography, and ultrasonography. Annual screening for hepatic metastases was performed., Results: Eight tumors demonstrated apparent complete regression over 1 month to 14 months. The amelanotic portion of the mixed tumor flattened, whereas the height of the pigmented part remained stable at 2 mm. In 8 patients there has been no recurrence during follow-up of between 34 months and 81 months. One case developed 2 separate local recurrences at 21 months and 34 months. There were no serious complications, no patient lost vision after treatment, and none developed metastatic disease., Conclusion: In this series photodynamic therapy was highly effective in causing regression of posteriorly located amelanotic choroidal melanomas, without a detrimental effect on vision. While the short-term results are encouraging, there is some uncertainty regarding complete tumor destruction and long-term efficacy.

Objectives: To investigate the safety and efficacy of photodynamic therapy (PDT) using talaporfin sodium in patients with surgically, completely unresectable malignant gliomas with invasion into the eloquent areas of the brain associated with language and motor functions., Materials and Methods: Subjects consisted of consecutive 14 adult patients with malignant gliomas that were shown on preoperative diagnostic imaging to have invaded the eloquent areas of the brain. Of these, 6 patients had newly diagnosed tumors and 8 patients had recurrent tumors. In 15 craniotomy and tumor resection procedures, PDT was used as additional intraoperative treatment 24 h after 40 mg/m(2) of talaporfin sodium had been injected intravenously. After the tumor bulk had been resected as extensively as possible either 1 or 2 sites of probable tumor invasion in the bottom of resection cavity were irradiated superficially with a 664-nm diode laser for 180 s (27 J/cm(2)) at a power density of 150 mW/cm(2)., Results: PDT achieved a response rate of 80% at the treated sites in the 6 patients with newly diagnosed malignant gliomas. In these patients, the median progression-free survival time was 23 months. The median survival time in 3 patients who died was 26 months, and the remaining 3 patients survived for more than 3 years with a good Karnofsky Performance Scale (KPS). In the 8 patients with recurrent tumors who received PDT, their response rate was low (25.0%), their gliomas recurred 3 months after PDT, and their survival time was only 9 months following PDT. No adverse events directly attributable to PDT occurred in any patients. Protection against light was only required for approximately 3 days after PDT., Conclusion: We examined the safety and efficacy of PDT using talaporfin sodium as an additional intraoperative treatment for malignant glioma. PDT in addition to surgical resection achieved better therapeutic results than conventional protocols, especially in patients with newly diagnosed malignant gliomas. However, the current methodology has some limitations with respect to patients with recurrent tumors. Larger-scale studies are required to confirm the clinical feasibility of PDT plus surgery., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration., Design: Prospective, multicenter, double-masked, randomized, active-controlled trial., Participants: We included 255 patients with all types of active subfoveal choroidal neovascularization., Methods: Patients were randomized 1:1 to as-needed (pro re nata; PRN) combination (standard-fluence verteporfin 6 mg/m(2) PDT and ranibizumab 0.5 mg) or PRN ranibizumab monotherapy (sham infusion [5% dextrose] PDT and ranibizumab 0.5 mg). Patients received 3 consecutive monthly injections followed by PRN retreatments based on protocol-specific retreatment criteria., Main Outcome Measures: Mean change in best-corrected visual acuity (BCVA) from baseline to month 12, and the proportion of patients with treatment-free interval ≥3 months at any timepoint after month 2., Results: The mean change in BCVA at month 12 was +2.5 and +4.4 letters in the combination and monotherapy groups, respectively (P = 0.0048; difference: -1.9 letters [95% confidence interval, -5.76 to 1.86], for having achieved noninferiority with a margin of 7 letters). The proportion of patients with a treatment-free interval of ≥3 months at any timepoint after month 2 was high, but did not show a clinically relevant difference between the treatment groups. Secondary efficacy endpoints included the mean number of ranibizumab retreatments after month 2 (1.9 and 2.2 with combination and monotherapy, respectively [P = 0.1373]). The time to first ranibizumab retreatment after month 2 was delayed by 34 days (about 1 monthly visit) with combination (month 6) versus monotherapy (month 5). At month 12, mean ± standard error central retinal thickness decreased by 115.3±9.04 μm in the combination group and 107.7±11.02 μm in the monotherapy group. The mean number of verteporfin/sham PDT treatments was comparable in the 2 groups (combination, 1.7; monotherapy, 1.9). The safety profiles of the 2 groups were comparable, with a low incidence of ocular serious adverse events., Conclusions: The combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. The combination therapy was well tolerated., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD)., Design: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial., Participants: Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105)., Methods: Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months., Main Outcome Measures: Mean change in best-corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment-free interval of 3 months or longer., Results: Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (-7.90 to infinity); P = 0.0666; and 97.5% CI, (-8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 μm and 140.9 μm for the verteporfin SF and RF groups, respectively, and by 172.2 μm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases., Conclusions: Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Treatment failure at the primary site after chemoradiotherapy is a major problem in achieving a complete response. Photodynamic therapy (PDT) with porfimer sodium (Photofrin®) has some problems such as the requirement for shielding from light for several weeks and a high incidence of skin phototoxicity. PDT with talaporfin sodium (Laserphyrin) is less toxic and is expected to have a better effect compared with Photofrin PDT. However, Laserphyrin PDT is not approved for use in the esophagus. In this preclinical study, we investigated tissue damage of the canine normal esophagus caused by photoactivation with Laserphyrin., Methodology/principal Findings: Diode laser irradiation was performed at 60 min after administration. An area 5 cm oral to the esophagogastric junction was irradiated at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2) using a three-step escalation. The irradiated areas were evaluated endoscopically on postirradiation days 1 and 7, and were subjected to histological examination after autopsy. The areas injured by photoactivation were 52 mm(2), 498 mm(2), and 831 mm(2) after irradiation at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2), respectively. Tissue injury was observed in the muscle layer or even deeper at any irradiation level and became more severe as the irradiation dose increased. At 100 J/cm(2) both inflammatory changes and necrosis were seen histologically in extra-adventitial tissue., Conclusions/significance: To minimize injury of the normal esophagus by photoactivation with Laserphyrin, diode laser irradiation at 25 J/cm(2) appears to be safe. For human application, it would be desirable to investigate the optimal laser dose starting from this level.

Objectives: The verteporfin photodynamic therapy (VPDT) cohort study aimed to answer five questions: (a) is VPDT in the NHS provided as in randomised trials?; (b) is 'outcome' the same in the nhs as in randomised trials?; (c) is 'outcome' the same for patients ineligible for randomised trials?; (d) is VPDT safe when provided in the NHS?; and (e) how effective and cost-effective is VPDT?, Design: Treatment register., Setting: All hospitals providing VPDT in the NHS., Participants: All patients attending VPDT clinics., Interventions: Infusion of verteporfin followed by infrared laser exposure is called VPDT, and is used to treat neovascular age-related macular degeneration (nAMD). The VPDT cohort study advised clinicians to follow patients every 3 months during treatment or active observation, retreating based on criteria used in the previous commercial 'TAP' (Treatment of Age-related macular degeneration with Photodynamic therapy) trials of VPDT., Main Outcome Measures: The primary outcome was logarithm of the minimum angle of resolution monocular best-corrected distance visual acuity (BCVA). Secondary outcomes were adverse reactions and events; morphological changes in treated nAMD (wet) lesions; and for a subset of patients, 6-monthly contrast sensitivity, generic and visual health-related quality of life (HRQoL) and resource use. Treated eyes were classified as eligible for the TAP trials (EFT), ineligible (IFT) or unclassifiable (UNC)., Results: Forty-seven hospitals submitted data for 8323 treated eyes in 7748 patients; 4919 eyes in 4566 patients were treated more than 1 year before the last data submission or had completed treatment. Of 4043 eyes with nAMD in 4043 patients, 1227 were classified as EFT, 1187 as IFT and 1629 as UNC. HRQoL and resource use data were available for about 2000 patients. The mean number of treatments in years 1 and 2 was 2.3 and 0.4 respectively. About 50% of eyes completed treatment within 1 year. BCVA deterioration in year 1 did not differ between eligibility groups. EFT eyes lost 11.6 letters (95% confidence interval 10.1 to 13.0 letters) compared with 9.9 letters in VPDT-treated eyes in the TAP trials. EFT eyes had poorer BCVA at baseline than IFT and UNC eyes. Adverse reactions and events were reported for 1.4% of first visits - less frequently than those reported in the TAP trials. Associations between BCVA in the best-seeing eye with HRQoL and community health and social care resource use showed that the 11-letter difference in BCVA between VPDT and sham treatment in the TAP trials corresponded to differences in utility of 0.012 and health and social service costs of £60 and £92 in years 1 and 2, respectively. VPDT provided an incremental cost per quality-adjusted life-year (QALY) of £170,000 over 2 years., Conclusions: VPDT was administered less frequently than in the TAP trials, with less than half of those treated followed up for > 1 year in routine clinical practice. Deterioration in BCVA over time in EFT eyes was similar to that in the TAP trials. The similar falls in BCVA after VPDT across the pre-defined TAP eligibility groups do not mean that the treatment is equally effective in these groups because deterioration in BCVA can be influenced by the parameters that determined group membership. Safety was no worse than in the TAP trials. The estimated cost per QALY was similar to the highest previous estimate. Although VPDT is no longer in use as monotherapy for neovascular AMD, its role as adjunctive treatment has not been fully explored. VPDT also has potential as monotherapy in the management of vascular malformations of the retina and choroid and with trials underway in neovascularisation due to myopia and polypoidal choroidopathy., Funding: The National Institute for Health Research Health Technology Assessment programme.

Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers that locate in endocytic vesicles, and that upon activation by light induce a release of macromolecules from the endocytic vesicles. PCI has been shown to stimulate delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane. The preclinical evaluation of PCI has been performed with aluminum phthalocyanine disulfonate (AlPcS(2a)) as photosensitizer. AlPcS(2a), due to its large number of isomers potentially with batch-to-batch ratio variations, is not an optimal photosenstizer for clinical use. Disulfonated tetraphenyl chlorin (TPCS(2a)) has therefore been developed by di-imide reduction of disulfonated tetraphenyl porphine (TPPS(2a)). The synthesized TPCS(2a) contains 3 isomers as shown by HPLC with low (<4%) inter-batch variation with respect to isomer formation, less than 0.5% (w/w) of the starting material TPPS(2a) and absorbs light at 652 nm. As prerequisites for a PCI photosensitizer TPCS(2a) was found to localize in intracellular granules assumed to be endocytic vesicles. In cells in culture TPCS(2a)-PCI induced activation of gelonin as seen by enhanced cytotoxicity, increased transfection efficacy by an enhanced green fluorescence protein (EGFP)-encoding plasmid, induced gene silencing by siRNA towards EGFP and induced in a synergistic manner tumor growth delay by TPCS(2a)-mediated PCI of bleomycin in CT26.CL25 carcinomas growing subcutaneously in athymic mice. TPCS(2a)-PCI of bleomycin was found superior to meso-tetraphenyl chlorin-based photodynamic therapy (mTHPC-PDT) with respect to inhibition of tumor growth. The tumor growth delay by PCI of bleomycin was independent of the time of bleomycin administration between 3 h prior to light to immediately after light, while bleomycin administered 24 h prior to or 24 h after the light exposure induced suboptimal or only additive effects on tumor growth delay respectively. TPCS(2a)-PDT and -PCI induced indistinguishably strong edema the first 3-4 days after TPCS(2a)-administration and only weak erythema the first day after TPCS(2a) administration. In contrast, mTHPC-PDT induced moderate edema the first 7 days after mTHPC administration, but strong erythema resulting in open wounds and escar formation the first 2-3 days after mTHPC administration. The pharmacokinetic properties of TPCS(2a) were evaluated in athymic mice. The plasma pharmacokinetics was best fit to a 2-compartment model with half-lives of 0.78 and 36 hrs. TPCS(2a) was found to be a clinically suitable PCI photosensitizer for photochemical activation of molecules that do not readily penetrate the cellular plasma membrane., (This journal is © The Royal Society of Chemistry and Owner Societies 2011)

Optically active nanomaterials promise to advance a range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. Here, we report the development of porphysomes; nanovesicles formed from self-assembled porphyrin bilayers that generated large, tunable extinction coefficients, structure-dependent fluorescence self-quenching and unique photothermal and photoacoustic properties. Porphysomes enabled the sensitive visualization of lymphatic systems using photoacoustic tomography. Near-infrared fluorescence generation could be restored on dissociation, creating opportunities for low-background fluorescence imaging. As a result of their organic nature, porphysomes were enzymatically biodegradable and induced minimal acute toxicity in mice with intravenous doses of 1,000 mg kg(-1). In a similar manner to liposomes, the large aqueous core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumours of xenograft-bearing mice and laser irradiation induced photothermal tumour ablation. The optical properties and biocompatibility of porphysomes demonstrate the multimodal potential of organic nanoparticles for biophotonic imaging and therapy.

Purpose: To compare verteporfin photodynamic therapy combined with intravitreal ranibizumab (combination therapy) versus ranibizumab monotherapy for management of neovascular age-related macular degeneration., Methods: Thirty patients (40 eyes) with neovascular age-related macular degeneration were prospectively allocated to combination therapy or monotherapy. In monotherapy, the induction phase consisted of 3 consecutive monthly ranibizumab injections (0.5 mg), while the combination therapy had a single session of photodynamic therapy with intravitreal ranibizumab. Follow-up treatment for either group consisted only of additional as-needed ranibizumab injections. The main outcome measure was that a proportion of eyes losing <15 letters of visual acuity after 12 months., Results: Except for 1 eye in combination therapy, all eyes in both groups lost <15 letters of visual acuity. At 12 months, there was a mean gain of +12 letters and +3.2 letters for monotherapy and combination therapy, respectively (relative percent change of 32% vs. 7%, P = 0.03). Anatomical improvement was similar in both groups. After induction, the time until ranibizumab retreatment was longer for combination therapy (P = 0.002) while ranibizumab injections were required more frequently with monotherapy (P = 0.015)., Conclusion: Ranibizumab monotherapy showed greater improvement in visual acuity versus combination therapy. However, combination therapy required fewer ranibizumab injections. Larger trials need to confirm the findings of this pilot study.

Several medications have been reported to cause punctal-canalicular stenosis, such as mitomycin C, docetaxel, 5-fluorouracil, and isotretinoin. To our knowledge, there have been no cases of verteporfin-associated punctal-canalicular stenosis described in the literature. We hereby present such a case.

Triamcinolone acetonide (TA) is one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The most important effects of TA consist in the stabilisation of the blood-retinal barrier and the down-regulation of inflammation. TA also has anti-angiogenic and anti-fibrotic properties. The peculiar characteristic of being well tolerated by ocular tissues and the capability to remain active for many months after a single intravitreal injection, make this drug a safe and effective alternative. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment of several ocular diseases such as uveitis, macular edema secondary to retinal vasculature disease, neovascularisation and vitreoretinopathy. In this paper, we review all the available evidence of its use in AMD as mono-therapy or in combination with other treatments, and we discuss which role TA will play in the treatment of AMD in the future. The first experiences with IVTA as monotherapy for the treatment of exudative AMD reported a positive outcome in transiently reducing the leakage from CNV. However, in the long-term follow-up, IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect found 3 months after the treatment. Consequently, studies using the combination of IVTA and photodynamic therapy (PDT), which acts synergistically, were performed. They reported to improve vision and to reduce the number of re-treatments with PDT. A large number of publications confirmed the positive synergic role of combining TA and PDT (therapies) for the treatment of all types of CNV: classic or predominantly classic, occult or minimally classic and RAP (Retinal Angiomatous Proliferation) lesions. The advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Nevertheless, cataract surgery may stimulate the development of CNV (result in stimulating CNV). However, in large, randomized, clinical trials on combination therapy of TA and PDT, visual acuity failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone. Some authors reported an increased risk of developing macular atrophy after the combination therapy with IVTA and PDT. Reduction of the PDT fluence rate in association with the use of steroids resulted in reducing the risk of macular atrophy and in a better visual acuity outcome. The introduction of anti-VEGF-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a higher proportion of patients, previously limited to minimizing vision loss. Anti-VEGF therapy also resulted in superior visual improvement compared to all types of combination therapy with IVT and PDT. Nevertheless, anti-VEGF monotherapy also has many limitations due to the need of repetitive treatments, increased costs and tachyphylaxis. Treatment regimens involving TA in combination therapy with anti-VEGF and PDT may preserve benefits for substantially longer periods. A question remains open on whether a combination treatment with anti-VEGF, triamcinolone and/or PDT may be a treatment option in patients with exudative AMD, by offering, with one cycle of therapy, functional VA benefits comparable to those observed with continued monthly anti-VEGF therapy. Further trials, of higher scientific significance, are needed to study the potential of these treatment options.

Aim: To investigate the efficacy of a combined intravitreal therapy with prior photodynamic therapy (PDT) in patients with wet age-related macular degeneration., Methods: Fifty-two patients (mean age: 72.7 years) with predominantly classic choroidal neovascularization received low-fluence PDT (42 J/cm2 for 72 s), followed 24 h later by a 0.4-ml core pars plana vitrectomy with intravitreal injection of dexamethasone (0.8 mg) and bevacizumab (1.25 mg). The best-corrected visual acuity (BCVA; 6 m Snellen), central macular thickness (optical coherence tomography), intraocular pressure and the need for retreatment were assessed., Results: BCVA changed significantly (vs. baseline) at 3 months (+0.11), 9 months (+0.19) and 14 months (+0.16). At the end of the follow-up period, BCVA had improved by > 0.1 in the majority of the patients (72.9%), and the mean central retinal thickness had decreased by -44.3% (-211 μm). The retreatment rate was 25%. No increase in intraocular pressure or other adverse event was reported., Conclusions: The pharmacological effects of the drugs, the low-fluence PDT, and the physiological effects of the therapy may have contributed to the sustainability of the therapeutic benefits., (Copyright © 2011 S. Karger AG, Basel.)

Purpose: To evaluate the efficacy and safety of triple therapy with intravitreal anti-vascular-endothelial-growth-factor (VEGF) antibody, dexamethasone and verteporfin photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD)., Methods: Retrospective, comparative, interventional study. Records of treatment-naïve patients who received intravitreal bevacizumab or ranibizumab in monotherapy or in combination with dexamethasone and full-fluence verteporfin PDT in triple therapy were reviewed. logMAR visual acuity, foveal thickness (FT) on optical coherence tomography, intraocular pressure and endophthalmitis occurrence were recorded., Results: Sixty-one eyes were included in the triple-therapy group, 40 eyes were included in the monotherapy group. The mean follow-up was 14.1 ± 3.4 months in the triple-therapy group and 16.3 ± 4.1 months in the monotherapy group. The triple-therapy group enjoyed a lower total number of treatments (1.92 ± 0.44 vs. 3.12 ± 0.37, p < 0.001) and a longer time before first retreatment (5.4 ± 3.3 vs. 3.6 ± 2.5 months, p = 0.001). A significant improvement of visual acuity and FT was present in both groups during the 12 months following first treatment. No adverse effects were observed., Conclusion: The combination of intravitreal bevacizumab or ranibizumabwith dexamethasone and full-fluence PDT for exudative AMD provided visual and anatomic improvement and a good safety profile. Triple therapy may reduce the number of retreatments when compared to anti-VEGF alone., (Copyright © 2010 S. Karger AG, Basel.)

Photodynamic therapy (PDT) induces damage to the endothelium, which can lead to increased vascular permeability and, under intensive PDT conditions, even to platelet aggregation, vasoconstriction, and blood flow stasis. Eventually, ischemia, hypoxia, and inflammation can occur, resulting in angiogenesis. We studied the sequence of the vascular events after Visudyne-PDT in the chicken chorioallantoic membrane (CAM) at day 11 of development. Using epi-fluorescence microscopy, we monitored the regrowth of capillaries in the PDT treated area. Immediately after irradiation, the treatment resulted in blood flow arrest. And 24 h post PDT, sprouting of new blood vessels was observed at the edge of the PDT zone. Neovessels looping out from the edge of the PDT zone gave rise to specialized endothelial tip structures guiding the vessels towards the center of the treated area. At 48 h almost all of the treated area was repopulated with functional but morphologically altered vasculature. These observations also showed reperfusion of some of the vessels that had been closed by the PDT treatment. CAM samples were immunohistochemically stained for Ki-67 showing proliferation of endothelial cells in the PDT area. Also, several markers of immature and angiogenic blood vessels, such as αVβ3-integrin, vimentin and galectin-1, were found to be enhanced in the PDT area, while the endothelial maturation marker intercellular adhesion molecule (ICAM)-1 was found to be suppressed. These results demonstrate that the new vascular bed is formed by both neo-angiogenesis and reperfusion of existing vessels. Both the quantitative real-time RT-PCR profile and the response to pharmacological treatment with Avastin, an inhibitor of angiogenesis, suggest that angiogenesis occurs after PDT. The observed molecular profiling results and the kinetics of gene regulation may enable optimizing combination therapies involving PDT for treatment of cancer and other diseases.

"Radachlorin"(®), also known in the EU as Bremachlorin, a composition of 3 chlorophyll a derivatives in an aqueous solution, was introduced into the Russian Pharmacopoeia. Its GMP (Good Manufacturing Practice) facility based manufacturing method was patented. Laboratory experiments and clinical phase I were performed. Protocols were designed for PDT of basal cell carcinoma of the skin to result in GCP (Good Clinical Practice)-conformed randomized phase II clinical studies. "Radachlorin"(®) solution for intravenous infusions 0.35% 10mL in the doses of 0.5-0.6 and 1.0-1.2mg/kg and a gel for topical application 0.1% 25g in the dose of 0.1g/cm(2) were photoactivated by 2.5W 662nm semiconductor laser "LAKHTA-MILON(®)" (St. Petersburg, Russia) in light doses of 200, 300 (solution), 400, 600, 800 (gel) J/cm(2). Safety study showed no side effects and a good tolerability of "Radachlorin"(®) by patients. There was no normal skin/subdermal tissue damage after both laser and sun light exposure. The main part (98%) of the drug was excreted or metabolized in the first 48h. Drug administration at a dose of 1.0-1.2mg/kg and irradiation at 3h with 662±3nm light at a dose of 300J/cm(2) (solution) and 4 PDT sessions at an interval of 1 week with 3h gel exposure, followed by 400J/cm(2) light exposure (gel) were found to be the optimal treatment regimes. Having successfully passed clinical trials, "Radachlorin"(®) achieved marketing authorization in Russia in 2009 and a conditional approval in South Korea in 2008. It is a candidate for phase III clinical trials in the EC and may be commercialized as a prospective second-generation photosensitizer., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In this report, spectral-domain optical coherence tomography (OCT) was used to characterize the acute morphologic alterations that occur when photodynamic therapy with verteporfin results in an acute severe visual decrease. The clinical and imaging records of a patient with neovascular age-related macular degeneration who suffered this complication were reviewed. Using spectral-domain OCT, two relatively distinct subretinal fluid compartments were visualized: a sparsely hyperreflective pocket of subretinal fluid overlying the fibrovascular pigment epithelial detachment, consistent with fibrinous exudation, and a more homogeneously hyporeflective compartment at the periphery of the choroidal neovascular lesion, consistent with serous exudation. The higher axial resolution, and greater sensitivity, of spectral-domain OCT allows improved visualization of the subretinal space. As experience with spectral-domain OCT grows, new parameters will emerge-such as those related to subretinal fluid-that will facilitate improvements in both the qualitative and quantitative evaluation of macular disease., (Copyright 2010, SLACK Incorporated.)

Purpose: The purpose of this study was to evaluate the efficacy of verteporfin photodynamic therapy on the treatment of polypoidal choroidal vasculopathy., Methods: A prospective, nonrandomized institutional study was conducted involving 42 eyes of 38 patients with newly diagnosed symptomatic polypoidal choroidal vasculopathy treated exclusively with photodynamic therapy. Twenty-seven eyes completed 3 years of follow-up. Subjects were observed every 3 months with evaluation of best-corrected visual acuity (BCVA), retinography, and fluorescein and indocyanine green angiography. Treatment was given whenever the patient exhibited subfoveal exudation on fluorescein angiography., Results: Mean BCVA was 0.91 +/- 0.33 logarithm of the minimum angle of resolution on the initial visit and 0.93 +/- 0.39 on the 36-month visit. Patients were submitted to an average of 3.19 treatment sessions. On the final evaluation at 36 months, 14.8% of the treated eyes improved their BCVA by at least 0.3 logarithm of the minimum angle of resolution, 74.1% had no significant loss of BCVA, and 25.9% lost >or=0.3 logarithm of the minimum angle of resolution. Recurrences were frequent (59.3% of the eyes at 3 years of follow-up), responded well to retreatment, and were not associated with additional BCVA loss., Conclusion: Photodynamic therapy remains a good option for management of polypoidal choroidal vasculopathy. After 3 years, approximately three fourths of the treated eyes had no significant loss of vision, and 14.8% showed significant improvement in visual acuity.

Photodynamic inactivation is a rapidly developing antimicrobial treatment that employs a nontoxic photoactivatable dye or photosensitizer in combination with harmless visible light to generate reactive oxygen species that are toxic to cells. Tetrapyrroles (e.g., porphyrins, chlorins, bacteriochlorins) are a class of photosensitizers that exhibit promising characteristics to serve as broad-spectrum antimicrobials. In order to bind to and efficiently penetrate into all classes of microbial cells, tetrapyrroles should have structures that contain (i) one or more cationic charge(s) or (ii) a basic group. In this report, we investigate the use of new stable synthetic bacteriochlorins that have a strong absorption band in the range 720 to 740 nm, which is in the near-infrared spectral region. Four bacteriochlorins with 2, 4, or 6 quaternized ammonium groups or 2 basic amine groups were compared for light-mediated killing against a gram-positive bacterium (Staphylococcus aureus), a gram-negative bacterium (Escherichia coli), and a dimorphic fungal yeast (Candida albicans). Selectivity was assessed by determining phototoxicity against human HeLa cancer cells under the same conditions. All four compounds were highly active (6 logs of killing at 1 microM or less) against S. aureus and showed selectivity for bacteria over human cells. Increasing the cationic charge increased activity against E. coli. Only the compound with basic groups was highly active against C. albicans. Supporting photochemical and theoretical characterization studies indicate that (i) the four bacteriochlorins have comparable photophysical features in homogeneous solution and (ii) the anticipated redox characteristics do not correlate with cell-killing ability. These results support the interpretation that the disparate biological activities observed stem from cellular binding and localization effects rather than intrinsic electronic properties. These findings further establish cationic bacteriochlorins as extremely active and selective near-infrared activated antimicrobial photosensitizers, and the results provide fundamental information on structure-activity relationships for antimicrobial photosensitizers.

Background/aims: To determine the potential efficacy and safety of combined verteporfin photodynamic therapy (PDT) with ranibizumab for the treatment of polypoidal choroidal vasculopathy (PCV)., Methods: In this prospective, non-comparative, interventional study, 12 eyes from 12 patients that had active PCV were treated with PDT combined with three monthly intravitreal injections of ranibizumab. The patients were then monitored monthly with measurements of best-corrected visual acuity (BCVA) and central retinal thickness quantified by optical coherence tomography for 1 year. Indocyanine green angiography (ICGA) and fluorescein angiography were performed every 3 months. The eyes were re-treated with PDT and a ranibizumab injection, or with solely ranibizumab injection when indicated., Results: At month 12, the mean BCVA change from baseline was +12.3 letters (p=0.04). Eight patients (58.3%, p=0.02) had a BCVA gain of 15 letters or more. One patient (8.3%, p=1.0) had a BCVA loss of 15 letters or more. All patients underwent regression of polyps without recurrence. One patient experienced an insignificant subretinal haemorrhage. No other adverse event that could be attributed to the treatment was observed., Conclusions: This combination therapy showed encouraging results concerning improving vision, reducing the incidence of subretinal haemorrhage and reducing the recurrence of polyps when compared to previously published data that reported PDT monotherapy for PCV.

Purpose: To report a case of recurrent herpes simplex keratitis after verteporfin photodynamic therapy for corneal neovascularization., Methods: A 69-year-old man who had lipid keratopathy with corneal neovascularization secondary to herpes simplex keratitis in the right eye and who was treated with topical steroid received photodynamic therapy with verteporfin. Six neovascular areas in the cornea were treated consecutively to occlude new vessels and reduce the risk of allograft rejection after subsequent keratoplasty., Results: Three days after verteporfin photodynamic therapy, there was evidence of vascular occlusion. However, a herpetic epithelial ulcer was detected in the cornea. Ten days after treatment, the lesion progressed to a geographic ulcer. After topical and systemic acyclovir treatment, the lesion healed. Five months after treatment, penetrating keratoplasty and postoperative antiviral prophylaxis were performed. During a follow-up period of 12 months, the graft remained clear with visual acuity of 20/40., Conclusion: Herpes simplex keratitis can recur after verteporfin photodynamic therapy for corneal neovascularization.

Purpose: To report 1-year results of reduced-fluence photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) in Japanese patients., Design: Prospective interventional case series., Methods: In the present study, 28 treatment-naïve eyes of 28 consecutive patients underwent PDT with a reduced laser fluence of 25 J/cm(2). Patients were followed up at baseline and 1 week and 3, 6, 9, and 12 months after PDT. Choroidal perfusion changes were evaluated by indocyanine green angiography (ICGA) and leakage from PCV lesions and exudative changes by fluorescein angiography and optical coherence tomography. Treatment safety was assessed according to visual acuity (VA) and adverse events. The best-corrected VA (BCVA) obtained by Landolt ring tests was converted into the logarithm of the minimal angle of resolution (logMAR)., Results: At baseline, the mean logMAR BCVA was 0.45 (geometric mean: 7/20). At 12 months, the mean logMAR BCVA significantly improved to 0.29 (geometric mean: 10/20) (P = 0.0001). The logMAR BCVA was stable or improved by >or=0.2 in 26 eyes (93%) at 1-year follow-up. In 10 eyes with VA better than 20/40 at baseline, the mean logMAR BCVA was significantly improved compared with baseline at 12 months. Although 16 of 28 eyes (57%) showed mild to moderate nonperfusion of choriocapillaris in early ICGA at 1 week, 27 eyes (96%) showed recovery to pretreatment levels at 3 months. Mean number of treatment sessions during the 12 months was 1.3. No severe side effects related to treatment were encountered., Conclusions: Reduced-fluence PDT is an effective treatment for PCV and could improve vision even in eyes with VA better than 20/40., ((c) 2010 Elsevier Inc. All rights reserved.)