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

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

Modeling the effect of land use/land cover on nitrogen, phosphorous and dissolved oxygen loads in the Velhas River using the concept of exclusive contribution area.

Non-point source water pollution is a major problem in most parts of the world, but is also very difficult to quantify and control since it is not easily separated from point sources and can theoretically originate from the whole watershed. In this article, we evaluate the relationship between land use and land cover and four water pollution parameters in a watershed in Southeast Brazil. The four parameters are nitrate, total ammonia nitrogen, total phosphorous, and dissolved oxygen. To help concentrate on non-point source pollution, only data from the wet seasons of the time period (2001-2013) were analysed, based on the fact that precipitation causes runoff which is the main cause of diffuse pollution. The parameters measured were transformed into loads, which were in turn associated with an exclusive contribution area, so that every measuring station could be considered independent. Analyses were also performed on riparian zones of different widths to verify if the effect of the land cover on the water quality of the stream decreases with the increased distance. Pearson correlation coefficients indicate that urban areas and agriculture/pasture tend to worsen water quality (source). Conversely, forest and riparian areas have a reducing effect on pollution (sink). The best results were obtained for total ammonia nitrogen and dissolved oxygen using the whole exclusive contribution areas with determination coefficients better than R (2)≈0.8. Nitrate and total phosphorous did not produce valid models. We suspect that the transformation delay from total ammonia nitrogen to nitrate might be an important factor for the poor result for this parameter. For phosphorous, we think that the phosphorous sink in the bottom sediment might be the most limiting factor explaining the failure of our models.

Mannose-6-phosphate receptor: a target for theranostics of prostate cancer.

The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6-phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic.

Synthesis and characterization of glycoconjugated porphyrin triphenylamine hybrids for targeted two-photon photodynamic therapy.

In order to avoid side effects at the time of cancer eradication to the patients, the selectivity of treatments has become of strategic importance. In the case of photodynamic therapy (PDT), two-photon absorption combined with active targeting of tumors could allow both spatial and chemical selectivity. In this context, we present the synthesis, spectroscopic, and biological properties of a series of porphyrin-triphenylamine hybrids with excellent singlet oxygen production capacities and good two-photon absorption.

Observation in the gas phase of the ligation of 1-methylimidazole to hemoprotein mimics.

Hemoprotein mimics, cobalt picket fence porphyrins have been prepared in the gas phase as neutral molecules for the first time. Their ligation properties have been studied with 1-methylimidazole and compared with those of other cobalt porphyrins, tetraphenyl porphyrin, and cobalt protoporphyrin IX chloride, in view of studying the sterical properties of the ligation. It is shown that the cobalt picket fence porphyrin can only accept one 1-methylimidazole ligand in contrast to less sterically crowded porphyrins like cobalt tetraphenylporphyrin that present two accessible ligation sites. The femtosecond dynamics of these ligated systems have been studied after excitation at 400 nm, in comparison with the unligated ones. The observed transients are formed in much shorter times, 30 fs for the ligated species, as compared to free species (100 fs), supporting the porphyrin to metal charge transfer nature of these transients. The similar decays of the ligated transients <1 ps reveal the absence of photodissociation of the cobalt-1-methylimidazole bond at this step of evolution.

Assessment of the relevance of supported planar bilayers for modeling specific interactions between glycodendrimeric porphyrins and retinoblastoma cells.

Glycodendrimeric porphyrins seem promising photosensitizers usable in photodynamic therapy. Evidence of their ability to interact with an artificial supported bilayer membrane exhibiting a model sugar receptor has been previously shown. In the present work, the interaction of the glycodendrimeric porphyrins with retinoblastoma cells bearing the actual sugar receptor has been assessed by both classical cell cultures and an original approach using the quartz crystal microbalance (QCM-D). Our results showed that unlike cell cultures, QCM-D allowed analyzing the mechanism of interaction of the glycodendrimeric porphyrins with the sugar receptor. Not only was molecular recognition demonstrated, but our methodology also proved efficient to discriminate between the studied compounds, depending on the presence of carbohydrate, and the spacer length.

Carbohydrate-conjugated porphyrin dimers: synthesis and photobiological evaluation for a potential application in one-photon and two-photon photodynamic therapy.

We report the synthesis of bioconjugated zinc porphyrin dimers 1a-e designed as photosensitizers for one-photon and two-photon excited photodynamic therapy. These macrocycles are substituted with carbohydrate units (glucose, mannose, lactose) in order to target tumor cells over-expressing lectin membrane receptors. Polarity, singlet oxygen production and in vitro photocytotoxicity are studied to determine their photodynamic therapy potentiality.

Integrating remote sensing and machine learning to detect turbidity anomalies in hydroelectric reservoirs.

Monitoring water quality in reservoirs is essential for the maintenance of aquatic ecosystems and socioeconomic services. In this scenario, the observation of abrupt elevations of physicochemical parameters, such as turbidity and other indicators, can signal anomalies associated with the occurrence of critical events, requiring operational actions and planning to mitigate negative environmental impacts on water resources. This work aims to integrate Machine Learning methods specialized in anomaly detection with data obtained from remote sensing images to identify with high turbidity events in the surface water of the Três Marias Hydroelectric Reservoir. Four distinct threshold-based scenarios were evaluated, in which the overall performance, based on F1-score, showed decreasing trends as the thresholds became more restrictive. In general, the anomaly identification maps generated through the models ratified the applicability of the methods in the diagnosis of surface water in reservoirs in distinct hydrological contexts (dry and wet), effectively identifying locations with anomalous turbidity values.

Tumor targeting in photodynamic therapy. From glycoconjugated photosensitizers to glycodendrimeric one. Concept, design and properties.

In this paper, we discuss the evolution over the last 15 years in the Curie Institute of the concept, the development of the design and some properties of glycoconjugated photosensitizers with the aim to optimize the tumor targeting in photodynamic therapy. By this research, we have shown that specific interactions between a mannose-lectin and trimannosylglycodendrimeric porphyrins contributed to a larger extent than non-specific ones to the overall interaction of a glycosylated tetraarylporphyrin with a membrane. The studies of in vitro photocytotoxicity showed the relevance of the global geometry of the photosensitizer, the number and position of the linked glycopyranosyl groups on the chromophore and their lipophilicity. The two best compounds appeared to be porphyrins bearing three α-glycosyl groups on para-position of meso-phenyl via a flexible linker. Compound bearing α-manosyl moieties was evaluated successfully in two in vivo xenografted animal models of human retinoblastoma and colorectal cancers. Conversely, the presence on the chromophore of three sugars via a glycodendrimeric moiety induced a potential cluster effect, but decreased the in vitro photoefficiency despite a good affinity for a mannose-lectin.

Increased PDT Efficacy When Associated with Nitroglycerin: A Study on Retinoblastoma Xenografted on Mice.

PURPOSES: The aim of the study was to assess the efficacy of a treatment protocol that combines photodynamic therapy (PDT) and nitroglycerin (NG) on human retinoblastoma tumors xenografted on mice. We aimed to increase the PDT efficiency (in our least treatment-responsive retinoblastoma line) with better PS delivery to the tumor generated by NG, which is known to dilate vessels and enhance the permeability and retention of macromolecules in solid tumors. METHODS: In vivo follow-up of the therapeutic effects was performed by sodium MRI, which directly monitors variations in sodium concentrations non-invasively and can be used to track the tumor response to therapy. NG ointment was applied one hour before PDT. The PDT protocol involves double-tumor targeting, i.e., cellular and vascular. The first PS dose was injected followed by a second one, separated by a 3 h interval. The timelapse allowed the PS molecules to penetrate tumor cells. Ten minutes after the second dose, the PS was red-light-activated. RESULTS: In this study, we observed that the PDT effect was enhanced by applying nitroglycerin ointment to the tumor-bearing animal's skin. PDT initiates the bystander effect on retinoblastomas, and NG increases this effect by increasing the intratumoral concentration of PS, which induces a higher production of ROS in the illuminated region and thus increases the propagation of the cell death signal deeper into the tumor (bystander effect).

A strategy for the targeting of photosensitizers. Synthesis, characterization, and photobiological property of porphyrins bearing glycodendrimeric moieties.

This paper describes the conception, synthesis, and characterization of new tetrapyrrolic chromophores bearing glycodendrimeric moieties inducing a potential increase of tumor targeting by a cluster effect. Two families of monoglycodendrimeric photosensitizers bearing three glycosyl units were designed, prepared with an acceptable overall efficiency and characterized by NMR, UV-visible, and fluorescence spectroscopies. The polarity and log P were evaluated by HPLC and the stir-flask method, respectively. The in vitro photoefficiency against two human tumor cell lines was assessed. The presence of the glycodendrimeric group does not appear to increase the tumor in vitro targeting.

Influence of carbohydrate biological vectors on the two-photon resonance of porphyrin oligomers.

We propose a spectroscopic study of π-conjugated porphyrin dimers and a triphenylamine centered trimer bearing monoethyleneglycol-peracetylated α-mannose targeting moieties, which were synthesized for application to two-photon absorption photodynamic therapy (2PA-PDT). The collected spectroscopic data are explained through comparison with previous results obtained on similar nonvectorized analogues. It appears that the different shifts and variations in linear and nonlinear absorption and emission bands are mainly due to an increased twist between the tetrapyrrolic units. The 2PA properties of the triphenylamine-centered trimer have been studied, and two fluorescence emission bands are observed that seem to originate from two different 2PA excitation pathways. These results have important implication for the design of new vectorized photosensitizers for 2PA-PDT.

New strategy for targeting of photosensitizers. Synthesis of glycodendrimeric phenylporphyrins, incorporation into a liposome membrane and interaction with a specific lectin.

Two glycodendrimeric phenylporphyrins were synthesized and their interaction with phospholipids was studied at the air-water interface and in liposome bilayers; such liposomes bearing glycodendrimeric porphyrin could constitute an efficient carrier for drug targeting in photodynamic therapy.

Mannose-targeted mesoporous silica nanoparticles for photodynamic therapy.

Functionalisation of MSN with mannose for PDT applications dramatically improved the efficiency of PDT on breast cancer cells.

An Evaluation of Radarsat-1 and ASTER Data for Mapping Veredas (Palm Swamps).

Veredas (palm swamps) are wetland complexes associated with the Brazilian savanna (cerrado) that often represent the only available source of water for the ecosystem during the dry months. Their extent and condition are mainly unknown and their cartography is an essential issue for their protection. This research article evaluates some of the fine resolution satellite data both in the radar (Radarsat-1) and optical domain (ASTER) for the delineation and characterization of veredas. Two separate approaches are evaluated. First, given the known potential of Radarsat-1 images for wetland inventories, the automatic delineation of veredas is tested using only Radarsat-1 data and a Markov random fields region-based segmentation. In this case, to increase performance, processing is limited to a buffer zone around the river network. Then, characterization of their type is attempted using traditional classification methods of ASTER optical data combined with Radarsat-1 data. The automatic classification of Radarsat data yielded results with an overall accuracy between 62 and 69%, that proved reliable enough for delineating wide and very humid veredas. Scenes from the wet season and with a smaller angle of incidence systematically yielded better results. For the classification of the main vegetation types, better results (overall success of 78.8%) were obtained by using only the visible and near infrared (VNIR) bands of the ASTER image. Radarsat data did not bring any improvement to these classification results. In fact, when using solely the Radarsat data from two different angle of incidence and two different dates, the classification results were low (50.8%) but remained powerful for delineating the permanently moist riparian forest portion of the veredas with an accuracy better than 75% in most cases. These results are considered good given the width of some types often less than 50 m wide compared with the resolution of the images (12.5 - 15 m). Comparing the classification results with the Radarsat-generated delineation allows an understanding of the relation between synthetic aperture radar (SAR) backscattering and vegetation types of the veredas.

Retinoblastoma membrane models and their interactions with porphyrin photosensitisers: An infrared microspectroscopy study.

Fourier Transform Infrared (FTIR) microspectroscopy was used to highlight the interactions between two photosensitisers (PS) of different geometries, TPPmOH4 and a glycoconjugated analogous, TPPDegMan, and lipid bilayers modelling retinoblastoma cell membranes. Retinoblastoma is a rare disease occurring in young infants, for whom conservative treatments may present harmful side-effects. Photodynamic therapy (PDT) is expected to induce less side-effects, as the photosensitiser is only activated when the tumour is illuminated. Since efficiency of the treatment relies on photosensitiser penetration in cancer cells, bilayers with three lipid compositions - pure SOPC, SOPC/SOPE/SOPS/Chol (56:23:11:10) and SOPC/SOPE/SOPS/Chol/CL (42:32:9:8:6) - were used as plasma and mitochondria model membranes. FTIR spectra showed that the interaction of the PSs with the lipid bilayers impacted the lipid organization of the latter, causing significant spectral variations. Both studied photosensitisers inserted at the level of lipid hydrophobic chains, increasing chain fluidity and disorder. This was confirmed by surface pressure measurements. Photosensitisers - TPPmOH4 more than TPPDegMan - also interacted with the polar region of the bilayer, forming hydrogen bonds with phosphate groups that induced major shifts of phosphate absorption bands. This difference in PS interaction with moieties in the polar region was more pronounced with the models with complex lipid composition.

Development of strategies for the regiocontrolled synthesis of meso-5,10,20-triaryl-2,3-chlorins.

Triglycoconjugated photosensitizers show promise for use in the photodynamic therapy-based treatment of cancer. Two different routes have been studied for the regioselective preparation of 5,10,20-meso-triphenyl-2,3-chlorin, 9a, and 5,10,20-meso-tri(4-isopropyloxyphenyl)-2,3-chlorin, 9b. The main issue was to control the placement of the partially reduced pyrrole ring in the more hindered environment in the triarylchlorin products.

Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles for two-photon photodynamic therapy or photoacoustic imaging.

Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles (BSPOR and BSPHT) were prepared. Their endocytosis in MCF-7 cancer cells was shown with two-photon excited fluorescence (TPEF) imaging. With two-photon excited photodynamic therapy (TPE-PDT), BSPOR was more phototoxic than BSPHT, which in contrast displayed a very high signal for photoacoustic imaging in mice.

Photodynamic efficiency of diethylene glycol-linked glycoconjugated porphyrins in human retinoblastoma cells.

Photodynamic therapy (PDT) is emerging as a new strategy for the conservative treatment of hereditary retinoblastoma. The glycoconjugated porphyrins TPP(p-Deg-O-alpha-GalOH)(3), TPP(p-Deg-O-beta-GalOH)(3), TPP(p-Deg-O-alpha-ManOH)(3), and their S-analogues were synthesized to obtain efficient photosensitizers with some retinoblastoma cell affinity. In these systems, a sugar motif and porphyrin core were linked by a diethylene glycol spacer (Deg). Cellular uptake, localization, and photoactivity have been examined in human retinoblastoma cells (Y79). After preincubation with corresponding glycosylated albumin, the uptake of TPP(p-Deg-O-beta-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) was 40-45% inhibited, indicating a possible cell-sugar-receptor saturation. High photoactivity was observed for the two alpha-galacto/manno porphyrins 8 and 10 (LD(50) = 0.05 and 0.35 muM, respectively) at 514 nm and low fluence (1 J/cm(2)). Analysis by MALDI-TOF mass spectrometry only indicated a small metabolic cleavage of the O-glycoconjugates and a good stability of the S-glycoside porphyrins. On the basis of these in vitro data, TPP(p-Deg-O-alpha-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) were selected for in vivo studies.

Pharmacokinetics of a tri-glucoconjugated 5,10,15-(meta)-trihydroxyphenyl-20-phenyl porphyrin photosensitizer for PDT. A single dose study in the rat.

Photodynamic therapy (PDT) involves a non invasive treatment of small and superficial cancers using a photosensitive drug and light to kill tumoral cells. 5,10,15-meso-tri-(meta-O-beta-D-glucosyloxyphenyl)-20-phenylporphyrin [m-TPP(glu)3] is a new photosensitizer (PS) with more enhanced photocytotoxicity relative to 5,10,15,20-meso-tetra-(meta-hydroxyphenyl) chlorin [m-THPC] (Foscan). It was injected intravenously once to healthy rats at three different doses (0.25, 0.5 and 1 mg kg(-1)) and compared to m-THPC (0.3 mg kg(-1)). Pharmacokinetic parameters for both photosensitizers were derived from plasma concentration-time data using a non-compartmental analysis and a two-compartment pharmacokinetic model. m-TPP(glu)3 is more rapidly eliminated throughout the organism than m-THPC. Its mean plasma clearance is 19 mL h(-1) kg(-1) (6 mL h(-1) kg(-1) for m-THPC), and its mean residence time is 5h (20 h for m-THPC). The area under curve (AUC) and initial mean serum concentration (C0) were found to be proportional to the dose. As for Foscan, no metabolite of m-TPP(glu)3 was detected in plasma. The biodistribution study demonstrates that the most significant amount of m-TPP(glu)3 was concentrated in organs such as lung, liver and spleen which are rich in reticulo-endothelial cells. Maximum concentrations were reached in organs 14 h after IV administration. At 48 h, the photosensitizer was essentially eliminated from all organs. Because of its shorter elimination time, m-TPP(glu)3 is more attractive than m-THPC as a PDT agent since secondary side effects of shorter duration could be expected.