BODIPY appended copper(II) complexes of curcumin showing mitochondria targeted remarkable photocytotoxicity in visible light

Copper(II) complexes of BODIPY (borondipyrromethene) derivatives (L-1, L-2) and curcumin (Hcur), viz. Cu(L-1)(cur)]Cl (1) and Cu(L-2)(cur)]Cl (2), where L-1 and L-2 are the non-iodinated and diiodinated BODIPY appended dipicolylamine ligands, are prepared and characterized and their photocytotoxic activity in visible light studied. Binding to copper(II) has rendered stability to curcumin from its hydrolytic degradation in buffer medium. The complexes show mitochondrial localization in HeLa cells emphasizing the findings that both 1 and 2 are mitochondria-targeting complexes and induce cancer cell death. Complex 1 with a fluorophoric BODIPY moiety in L-1 gave IC50 values of 7.9(+/- 0.3) mu M in visible light (400-700 nm) and 29.1(+/- 0.5) mu M in the dark. Complex 2 having a diiodo BODIPY moiety in L-2 as a photosensitizer gave IC50 values of 3.8(+/- 0.2) mu M in visible light and 32.1(+/- 0.4) mu M in the dark. The PDT effect of 2 is comparable to that of Photofrin (R), an FDA approved PDT drug. Cell death follows an apoptotic pathway with the formation of reactive oxygen species (ROS).

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

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

Histological analyses of thermal effect caused by 1.2 W diode laser irradiation at rat periodontal pockets

The aim of this in vivo study was to evaluate the thermal effects caused by 810 nm 1.2 W diode laser irradiation of periodontal tissues. Despite all data available concerning the laser application for periodontal treatment, one of the most relevant challenges is to prevent the harmful tissue heating induced by different clinical protocols. Periodontal pockets were induced at molars in 96 rats. Several irradiation powers under CW mode were investigated: 0, 400, 600, 800, 1000, 1200 mW. The pockets were irradiated using a 300 A mu m frontal illumination fiber. The animals were killed at 4 or 10 days after irradiation. The mandible was surgically removed and histologically processed. The histological sections stained with H/E demonstrated that irradiation parameters up to 1000 mW were thermally safe for the periodontal tissues. The sections stained with Brown & Brenn technique evidenced bacteria in the periodontal tissues. Consequently, the diode laser irradiation as a unique treatment was not capable to eliminate bacteria of the biofilm present in the pockets. According to the methodology used here, it was concluded that the thermal variation promoted by a diode laser can cause damage to periodontal tissues depending on the energy density used. The 1.2 W diode laser irradiation itself does not control the bacteria present in the biofilm of the periodontal pockets without mechanical action. The knowledge of proper high intensity laser parameters and methods of irradiation for periodontal protocols may prevent any undesirable thermal damage to the tissues.

Can efficiency of the photosensitizer be predicted by its photostability in solution?

We have investigated a possible correlation between the photostability and photodynamic efficacy for different photosensitizers; hematoporphyrin derivatives and chlorines. To perform such analysis, we combined the depth of necrosis (d (nec)) measurement, expressed by the light threshold dose and a photodegradation parameter, measured from investigation of photosensitizer degradation in solution. The d (nec) analysis allows us to determine the light threshold dose and compare its value with the existent results in the literature. The use of simple models to understand basic features of Photodynamic Therapy (PDT) may contribute to the solid establishment of dosimetry in PDT, enhancing its use in the clinical management of cancers and others lesions. Using hematoporphyrin derivatives and chlorines photosensitizers we investigated their properties related to the photodegradation in solution and the light threshold dose (D (th)) in rat livers.

Phototransformation of hematoporphyrin in aqueous solution: Anomalous behavior at low oxygen concentration

The photoactivation of a photosensitizer is the initial step in photodynamic therapy (PDT) where photochemical reactions result in the production of reactive oxygen species and eventually cell death. In addition to oxidizing biomolecules, some of these photochemical reactions lead to photosensitizer degradation at a rate dependent on the oxygen concentration among other factors. We investigated photodegradation of Photogem A (R) (28 mu M), a hematoporphyrin derivative, at different oxygen concentrations (9.4 to 625.0 mu M) in aqueous solution. The degradation was monitored by fluorescence spectroscopy. The degradation rate (M/s) increases as the oxygen concentration increases when the molar ratio of oxygen to PhotogemA (R) is greater than 1. At lower oxygen concentrations (< 25 mu M) an inversion of this behavior was observed. The data do not fit a simple kinetic model of first-order dependence on oxygen concentration. This inversion of the degradation rate at low oxygen concentration has not previously been demonstrated and highlights the relationship between photosensitizer and oxygen concentrations in determining the photobleaching mechanism(s). The findings demonstrate that current models for photobleaching are insufficient to explain completely the effects at low oxygen concentration.

A combination of techniques to evaluate photodynamic efficiency of photosensitizers

Photodynamic therapy, used mainly for cancer treatment and microorganisms inaction, is based on production of reactive oxygen species by light irradiation of a sensitizer. Hematoporphyrin derivatives as Photofrin (R) (PF) Photogem (R) (PG) and Photosan (R) (PF), and chlorin-c6-derivatives as Photodithazine (R)(PZ), have suitable sensitizing properties. The present study provides a way to make a fast previous evaluation of photosensitizers efficacy by a combination of techniques: a) use of brovine serum albumin and uric acid as chemical dosimeters; b) photo-hemolysis of red blood cells used as a cell membrane interaction model, and c) octanol/phosphate buffer partition to assess the relative lipophilicity of the compounds. The results suggest the photodynamic efficient rankings PZ > PG >= PF > PS. These results agree with the cytotoxicity of the photosensitizers as well as to chromatographic separation of the HpDs, both performed in our group, showing that the more lipophilic is the dye, the more acute is the damage to the RBC membrane and the oxidation of indol, which is immersed in the hydrophobic region of albumin.

Photostability of different chlorine photosensitizers

In this paper, we report the photodegradation of three different chlorine photosensitizers (Photoditazine (R), Radachlorin (R), and Foscan (R)). The photosensitizer degradation was analyzed by changes in the fluorescence spectrum during illumination. The rate of fluorescence variation was normalized to the solution absorption and the photon energy resulting in the determination of the necessary number of photons to be absorbed to induce photosensitizer photodegradation. The parameter for rate of the molecules decay, the photon fluence rate and optical properties of the solution allow us to determine the photosensitizer stability in solution during illumination. The results show that the order of susceptibility for photodegradation rate is: Radachlorin (R) < Photoditazine (R) < Foscan (R). This difference in the photodegradation rate for Foscan can be explained by the high proportion of aggregates in solution that inhibit the photo-oxidative process that impede the singlet oxygen formation. We hypothesize that there is a correlation between photodegradation rate and photodynamic efficacy witch is governed by the singlet oxygen formation responsible for the most relevant reaction of the cell death photodynamic induction. Then its is important to know the photostability of different types of drugs since the photodegradation rate, the photodegradation as well as the photodynamic efficacy are strong correlated to the oxygen concentration in the tissue.

Aggregation susceptibility on phototransformation of hematoporphyrin derivatives

Photosensitizers used in PDT suffer degradation by light. In this work, photobleaching of Photogem((R)) (PG), Photofrin((R)) (PF), and Photosan((R)) (PS), hematoporphyrin derivatives, were induced by light in the presence or absence of 1% Triton X-100. The degradation efficiency in the absence of 1% Triton X-100 follows the sequence: Pf > PF > Ps, which means that PF presented a greater degradation than PF and PS. Forever, in the presence of the surfactant the degradation efficiency is different: PF congruent to PS > PF. Besides aggregation susceptibility, studies in cell culture (tumor and non tumor cells) and in animals (depth of necrosis) were performed, trying to correlate the stability of these photosensitizers with their photodynamic effect. The results suggest that PF presents higher light induced photo-cytotoxicity than PF and PS for both types of cells. For the depth of necrosis studies, more aggregated photosensitizer showed a longer time to accumulate in liver (30 min for PG, 120 h for PF and 720 h for PS). The, to establish an ideal dosimetry in PDT, one must consider the intrinsic physical chemistry characteristics of the photosensitizer as well as their ability to undergo photobleaching.

The experimental research of R-phycoerythrin subunits on cancer treatment: A new photosensitizer in PDT

The mouse tumor cell 5180 and human liver carcinoma cell SMC 7721 cells were first treated with R-PE and its subunits (alpha, beta, gamma subunits), then irradiated with Argon laser (496 nm, 28.8 J/cm(2)). Survival rate was measured by MTT method. In order to compare the phototoxicity in normal cells, the mouse marrow cells were treated with photofrin II and beta-subunit, irradiated with 45 J/cm(2) of light; survival rate was also measured by MTT method. The result showed that R-PE subunits had better PDT effect on s180 cells than R-PE and lower phototoxicity in marrow cells than photofrin II Flow cytometric analysis showed that PDT results in a growth inhibition and a G(0)-G(1) cell cycle arrest in SMC 7721 cells. The tumor cells inhibited by PDT in vivo were morphologically observed by TEM, the tumor cell death was daze to the occlusion of tumor blood vessels and inducement of cell programmed death in nuclei. Therefore, with the advantage in special fluorescence activity, loth molecular weight, good light absorbent character and weak phototoxicity, R-PE subunit is art attractive option for improving the selectivity of PDT.

Toxicity of photodynamic therapy with LED associated to Photogem (R): An in vivo study

The aims of this study were to evaluate the effects of PhotogemA (R)-mediated photosensitization on rat palatal mucosa and the biodistribution of the photosensitizer in this tissue. A solution of PhotogemA (R) (500 or 1000 mg/l) was applied to the palatal mucosa for 30 min and the exposure time to blue LED (460 nm) was 20 min (144 J/cm(2)). At 0, 1, 3, and 7 days, palatal mucosa was photographed for macroscopic analysis. After killing, the palate was removed for microscopic analysis. Thermal mapping evaluated temperature change in the tissue during irradiation. All experimental groups revealed intact mucosa in the macroscopic analysis. Tissue alterations were observed microscopically for only four out of 80 animals subjected to PDT. Fluorescence emitted by PhotogemA (R) was identified and was limited to the epithelial layer. A temperature increase from 35 to 41A degrees C was recorded. PhotogemA (R)- mediated PDT was not toxic to the rat palatal mucosa.

Confirmatory factor analysis of the Way of Coping Checklist-Revised (WCCL-R) in the Asian context

Industrial employment growth has been one of the most dynamic areas of expansion in Asia; however, current trends in industrialised working environments have resulted in greater employee stress. Despite research showing that cultural values affect the way people cope with stress, there is a dearth of psychometrically established tools for use in non-Western countries to measure these constructs. Studies of the "Way of Coping Checklist-Revised" (WCCL-R) in the West suggest that the WCCL-R has good psychometric properties, but its applicability in the East is still understudied. A confirmatory factor analysis (CFA) is used to validate the WCCL-R constructs in an Asian population. This study used 1,314 participants from Indonesia, Sri Lanka, Singapore, and Thailand. An initial exploratory factor analysis revealed that original structures were not confirmed; however, a subsequent EFA and CFA showed that a 38-item, five-factor structure model was confirmed. The revised WCCL-R in the Asian sample was also found to have good reliability and sound construct and concurrent validity. The 38-item structure of the WCCL-R has considerable potential in future occupational stress-related research in Asian countries.

Curvilinear relationships between the job demands-resources (JD-R) model, and work engagement : a police service case study

The current study aims to investigate the non-linear relationship between the JD-R model and work engagement. Previous research has identified linear relationships between these constructs; however there are strong theoretical arguments for testing curvilinear relationships (e.g., Warr, 1987). Data were collected via a self-report online survey from officers of one Australian police service (N = 2,626). Results demonstrated a curvilinear relationship between job demands and job resources and engagement. Gender (as a control variable) was also found to be a significant predictor of work engagement. The results indicated that male police officers experienced significantly higher job demands and colleague support than female officers. However, female police officers reported significantly higher levels of work engagement than male officers. This study emphasises the need to test curvilinear relationships, as well as simple linear associations, when measuring psychological health.

Innovation adoption and fit, linking R&D and industry

Significant sums of money are invested in developing technological innovations that have low levels and rates of adoption. Several approaches have been put forward in an effort to improve rates of adoption. This paper presents the results of study that examined the innovation fit of key technological innovations in the beef industry. Findings indicate that be assessing the innovation fit throughout the R&D process researchers and end users can collaborate to improve the innovation fit and the rate of adoption. The paper also put forward a model that demonstrates the linkages between R&D, adoption and innovation fit.

Railways, Urban Development and Town Planning in Britain: 1948–2008, Haywood R. Ashgate (2009). £65.00, ISBN: 9780754673927

This book is a thorough investigation of the relationship between land use planning and the railways in Britain, through review of the factors affecting the two sectors and their integration during the period of public ownership. The rationale behind the book is explained as a timely analysis of the dynamic correlation involving town planning and management of the railway in a period when growing congestion on the road network is forcing people to look for alternative modes and capacity is badly needed to accommodate this increased demand for travel. The book calls for a modal shift from road to rail for passenger and freight traffic.