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Concept: Photodynamic therapy

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BACKGROUND: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA). RESULTS: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods. CONCLUSIONS: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapyTrial registration: ClinicalTrials.gov NCT01570790.

Concepts: Clinical trial, Optics, Blood pressure, Retina, Macular degeneration, Photodynamic therapy, Combretastatin A-4, Combretastatin A-4 phosphate

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Introduction or backgroundThe hallmark of wet age-related macular degeneration (AMD) is choroidal neovascularization (CNV). The key cytokine involved in the pathogenesis of CNV is vascular endothelial growth factor (VEGF). Since 2005, antiVEGF therapy has revolutionized the management of this condition.Sources of dataA systematic computerized literature search was conducted on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/).Areas of agreementAntiVEGF therapy has resulted in improvement in visual function and performance. Currently, practitioners are spoilt for choice of these agents.Areas of controversyBevacizumab is unlicensed for intraocular use but has a better market share than ranibizumab in the treatment of wet AMD as it is approximately 40 times cheaper than ranibizumab, if aliquoted into smaller doses for intraocular use. This has stirred up questions on indemnity, safety, dosing, treatment regimen and quality control, despite the fact that well-designed clinical trials have shown that both drugs are equally effective. Another dilemma for the physicians is the choice of treatment regimens with antiVEGF agents that include fixed dosing, optical coherence tomography (OCT)-guided re-treatment, treat and extend or a combination of proactive and reactive dosing. Real-life outcomes of physician-dependent OCT-guided re-treatment with these agents are inferior to outcomes reported in clinical trials.Growing pointsA recently food and drug administration-approved antiVEGF agent, aflibercept, is rapidly becoming a popular choice as well-designed randomized clinical trials indicate that eight weekly fixed dosing of aflibercept is non-inferior to monthly ranibizumab.Areas timely for developing researchOptions for reducing the frequency of repeated intravitreal injections are being explored. Combination therapy with photodynamic therapy and epimacular brachytherapy seem scientifically plausible due to their synergistic effects. However, so far the results on these combinations have not shown any superior visual outcomes to antiVEGF monotherapy, and the practicalities of delivering these therapies are formidable. So, research into other novel therapeutic approaches such as pigment epithelium-derived factor and designed ankyrin repeat proteins are gaining momentum.

Concepts: Clinical trial, Vascular endothelial growth factor, Retina, Macular degeneration, Ranibizumab, Bevacizumab, Photodynamic therapy, Choroidal neovascularization

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Upconverting nanoparticles (UCNPs) have attracted considerable attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this work, a new and efficient NIR photosensitizing nanoplatform for PDT based on red-emitting UCNPs is designed. The red emission band matches well with the efficient absorption bands of the widely used commercially available photosensitizers (Ps), benefiting the fluorescence resonance energy transfer (FRET) from UCNPs to the attached photosensitizers and thus efficiently activating them to generate cytotoxic singlet oxygen. Three commonly used photosensitizers, including chlorine e6 (Ce6), zinc phthalocyanine (ZnPc) and methylene blue (MB), are loaded onto the alpha-cyclodextrin-modified UCNPs to form Ps@UCNPs complexes that efficiently produce singlet oxygen to kill cancer cells under 980 nm near-infrared excitation. Moreover, two different kinds of drugs are co-loaded onto these nanoparticles: chemotherapy drug doxorubicin and PDT agent Ce6. The combinational therapy based on doxorubicin (DOX)-induced chemotherapy and Ce6-triggered PDT exhibits higher therapeutic efficacy relative to the individual means for cancer therapy in vitro.

Concepts: Spectroscopy, Oxygen, Ultraviolet, Chemotherapy, Förster resonance energy transfer, Methylene blue, Singlet oxygen, Photodynamic therapy

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2-Demethoxy-2,3-ethylenediamino hypocrellin B (EDAHB) is a diamino-substituted hypocrellin B (HB) with high absorption of red light and high quantum yield of both singlet oxygen ((1)O(2)) and superoxide anions (O(2)(-)). Here we reported the cellular uptake, subcellular location, and cytotoxicity of EDAHB, as well as EDAHB-mediated photodynamic therapy (PDT) efficiency, and cell apoptosis. Results showed that EDAHB accumulated in HeLa cells rapidly up to 1h, with a subsequent decrease in the rate of uptake. EDAHB distributed with well-defined spots throughout the cytoplasm of the cells. EDAHB showed a much higher photopotentiation factor than HB. The phototoxicity of EDAHB to HeLa cells occurred via a mitochondria/caspase apoptosis pathway. This study showed EDAHB to be a promising candidate of photosensitizer for anti-tumor PDT.

Concepts: Protein, Oxygen, Cell, Apoptosis, Cell culture, Vesicle, Singlet oxygen, Photodynamic therapy

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Topical protoporphyrin (PpIX)-induced photodynamic therapy (PDT) relies on the penetration of the prodrug into the skin lesion and subsequent accumulation of the photosensitizer. Methyl aminolevulinate (MAL)-PDT is an established treatment for thinner and superficial non-melanoma skin cancers (NMSCs) but for the treatment of the thicker nodular basal cell carcinoma (nBCC) enhanced penetration of the prodrug is required. This study employed a new higher pressure, oxygen pressure injection (OPI) device, at the time of Metvix® application with a view to enhancing the penetration of MAL into the tumors. Each patient had Metvix® applied to a single nBCC followed by application of a higher pressure OPI device. Following different time intervals (0, 30, 60, 120 or 180min) the tumors were excised. The maximum depth and area of MAL penetration achieved in each lesion was measured using PpIX fluorescence microscopy. As expected, an increase in the depth of MAL-induced PpIX accumulation and area of tumor sensitized was observed over time; when the Metvix® cream was applied for 0, 30, 60, 120 and 180min the median depth of PpIX fluorescence was 0%, 21%, 26.5%, 75.5% and 90%, respectively and the median area of tumor sensitized was 0%, 4%, 6%, 19% and 60%, respectively. As the investigation presented here did not include a control arm, the relative depths of fluorescence observed in this study were statistically compared (using the non-parametric Mann Whitney U test) with the results of our previous study where patients had Metvix® cream applied either with or without the standard pressure OPI device. When the higher pressure OPI device was employed compared to without OPI this increase was observed to be greater following 30, 120, and 180min although overall not significantly (p=0.835). In addition, no significant difference between the higher pressure OPI device employed here and the previously investigated standard pressure OPI device was observed (p=0.403). However, when the results for both OPI devices were combined and compared to the standard treatment (no OPI employed) group, although the difference did not reach significance (p=0.531) a consistent and substantial increase in the depth of PpIX fluorescence was observed, therefore employment of an OPI device during topical MAL-PDT protocols warrants further investigation as a technique for enhancing MAL penetration.

Concepts: Cancer, Statistical significance, Squamous cell carcinoma, Basal cell carcinoma, Skin cancer, Photodynamic therapy, Methyl aminolevulinate, Protoporphyrin IX

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BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with (3)O(2). In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.

Concepts: Fluorescence, Electron, Spectroscopy, Oxygen, Ultraviolet, Singlet oxygen, Photodynamic therapy, Triplet oxygen

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Gold nanorods with three different aspect ratios were prepared and their dual capabilities for two-photon imaging and two-photon photodynamic therapy have been demonstrated. These gold nanorods exhibit large two-photon absorption action cross-sections, about two orders of magnitude larger than small organic molecules, which makes them suitable for two-photon imaging. They can also effectively generate singlet oxygen under two-photon excitation, significantly higher than traditional photosensitizers such as Rose Bengal and Indocyanine Green. Such high singlet oxygen generation capability under two-photon excitation was ascribed to their large two-photon absorption cross-sections. Polyvinylpyrrolidone (PVP) coated gold nanorods displayed excellent biocompatibility and high cellular uptake efficiency. The two-photon photodynamic therapy effect and two-photon fluorescence imaging properties of PVP coated gold nanorods have been successfully demonstrated on HeLa cells in vitro using fluorescence microscopy and indirect XTT assay method. These gold nanorods thus hold great promise for imaging guided two-photon photodynamic therapy for the treatment of various malignant tumors.

Concepts: Protein, Oxygen, Cancer, Two-photon excitation microscopy, Aspect ratio, Singlet oxygen, Photodynamic therapy, Rose bengal

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Organically modified mesoporous silica nanoparticles (MSNs) containing rose bengal (RB), a xanthene dye, were successfully synthesized. RB-modified MSNs have shown a relevant photostability and a high efficiency in the photoproduction and delivery of singlet oxygen ((1) O2 ), which is particularly promising for photodynamic therapy (PDT) applications. In vitro tests have evidenced that RB-MSNs are able to reduce cell proliferation in one of the most aggressive skin cancer types (SK-MEL-28) after green-light irradiation.

Concepts: Oxygen, Carbon dioxide, Silicon, Mesoporous silica, Singlet oxygen, Photodynamic therapy, Triplet oxygen, Rose bengal

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Although photodynamic therapy (PDT) was discovered over a hundred years ago by its ability to destroy microorganisms, it has been developed mainly as a cancer therapy. In recent years, due to the inexorable rise in multi-antibiotic resistant strains of pathogens, PDT is being considered as a versatile antimicrobial approach to which microbial cells will not be able to develop resistance. The goal of this review is to survey the different classes of chemical compounds that have been tested as antimicrobial photosensitizers. Some of these compounds have been known for many years, while others have been rationally designed based on recently discovered structural principles. Tetrapyrrole-based compounds (some of which are approved as cancer therapies) that efficiently generate singlet oxygen are more efficient and broad-spectrum when they bear cationic charges, As the macrocycle structure moves from porphyrins to chlorins to phthalocyanines to bacteriochlorins the long wavelength absorption moves to the near-infrared where tissue penetration is better. Four main types of natural products have been tested: curcumin, riboflavin, hypericin and psoralens. Phenothiazinium dyes, such as methylene blue and toluidine blue, have been tested, and some are clinically approved. A variety of non-phenothiazinium dyes with xanthene, triarylmethane and indocyanine structures have also been tested. New ring structures based on BODIPY, squaraine and fullerene cages can also mediate antimicrobial PDT. Finally the process of photocatalysis using titanium dioxide can also have medical uses. Designing new antimicrobial photosensitizers is likely to keep chemists engaged for a long time to come.

Concepts: Oxygen, Bacteria, Microbiology, Antibiotic resistance, Oxide, Methylene blue, Singlet oxygen, Photodynamic therapy

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Heavy atom effect and configuration are important for BODIPY derivatives to generate singlet oxygen (1O2) for photodynamic therapy. Herein, a series of BODIPY derivatives with different halogens were synthesized. 1O2 quantum yields (QYs) and MTT assay confirm that incorporation of more heavy atoms onto dimeric BODIPY can’t effectively enhance the 1O2 QYs. Rather, the dark toxicity increases. This phenomenon can be attributed to the competition of heavy atom effect and configuration of dimeric BODIPY. And the BODIPY derivative with two iodine atoms (BDPI) owns the highest 1O2 QYs (73%) and the lowest photo-toxicity IC50 (1 μM). Furthermore, in vivo study demonstrates that BDPI NPs can effectively inhibit tumor growth and can be used as a promising threanostic agent for photodynamic therapy in clinic.

Concepts: Oxygen, Quantum mechanics, Chemical bond, In vivo, Chemical element, Excited state, Singlet oxygen, Photodynamic therapy