Luzitin SA

Coimbra, Portugal

Luzitin SA

Coimbra, Portugal
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Dabrowski J.M.,Jagiellonian University | Urbanska K.,Jagiellonian University | Arnaut L.G.,University of Coimbra | Pereira M.M.,University of Coimbra | And 4 more authors.
ChemMedChem | Year: 2011

The invitro phototoxicity of a photostable, synthetic, water-soluble, halogenated bacteriochlorin, 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)bacteriochlorin (TCPBSO3H), toward mouse melanoma (S91) cells is ∼60-fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90% of S91 cells were killed in response to a light dose of 0.26Jcm-2 in the presence of [TCPBSO3H]=5μM. Invivo toxicity toward DBA mice is very low, even at doses of 20mgkg-1. Invivo pharmacokinetics and biodistribution of TCPBSO3H were studied in DBA mice with S91 tumors; 24h after intraperitoneal injection of 10mgkg-1, TCPBSO3H demonstrated preferential accumulation in S91 mouse melanoma, with tumor-to-normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90mWcm-2 diode laser irradiation at λ750nm for 20min (total light dose of 108Jcm-2), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Monteiro C.J.P.,University of Coimbra | Pina J.,University of Coimbra | Pereira M.M.,University of Coimbra | Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA
Photochemical and Photobiological Sciences | Year: 2012

The decay channels of the singlet excited states of halogenated sulfonamide tetraphenylporphyrins, chlorins and bacteriochlorins were fully characterized. It was found that the radiative rates and the internal conversion rates of the bacteriochlorins are lower than expected from the Strickler-Berg equation and from the energy-gap law, respectively. It is concluded that this family of bacteriochlorins can combine long-lived singlet states with photostability, which are desired properties to harvest near-infrared light. This journal is © The Royal Society of Chemistry and Owner Societies.

Dabrowski J.M.,Jagiellonian University | Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA
Photochemical and Photobiological Sciences | Year: 2015

Photodynamic therapy (PDT) requires a medical device, a photosensitizing drug and adequate use of both to trigger biological mechanisms that can rapidly destroy the primary tumour and provide long-lasting protection against metastasis. We present a multidisciplinary view of the issues raised by the development of PDT. We show how spectroscopy, photophysics, photochemistry and pharmacokinetics of photosensitizers determine the mechanism of cell death and clinical protocols. Various examples of combinations with chemotherapies and immunotherapies illustrate the opportunities to potentiate the outcome of PDT. Particular emphasis is given to the mechanisms that can be exploited to establish PDT as a systemic treatment of solid tumours and metastatic disease. © The Royal Society of Chemistry and Owner Societies 2015.

Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA | Formosinho S.J.,University of Coimbra
Pure and Applied Chemistry | Year: 2013

Theories of radiationless conversions and of chemical processes were employed to design better photosensitizers for photodynamic therapy (PDT). In addition to photostability and intense absorption in the near infrared, these photosensitizers were required to generate high yields of long-lived triplet states that could efficiently transfer their energy, or an electron, to molecular oxygen. The guidance provided by the theories was combined with the ability to synthesize large quantities of pure photosensitizers and with the biological screening of graded hydrophilicities/lipophilicities. The theoretical prediction that halogenated sulfon amide tetraphenylbacteriochlorins could satisfy all the criteria for ideal PDT photosensitizers was verified experimentally. © 2013 IUPAC.

Krzykawska-Serda M.,Jagiellonian University | Dabrowski J.M.,Jagiellonian University | Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA | And 4 more authors.
Free Radical Biology and Medicine | Year: 2014

Blood flow and pO2 changes after vascular-targeted photodynamic therapy (V-PDT) or cellular-targeted PDT (C-PDT) using 5,10,15,20-tetrakis(2,6- difluoro-3-N-methylsulfamoylphenyl) bacteriochlorin (F2BMet) as photosensitizer were investigated in DBA/2 mice with S91 Cloudman mouse melanoma, and correlated with long-term tumor responses. F2BMet generates both singlet oxygen and hydroxyl radicals under near-infrared radiation, which consume oxygen. Partial oxygen pressure was lowered in PDT-treated tumors and this was ascribed both to oxygen consumption during PDT and to fluctuations in oxygen transport after PDT. Similarly, microcirculatory blood flow changed as a result of the disruption of blood vessels by the treatment. A novel noninvasive approach combining electron paramagnetic resonance oximetry and laser Doppler blood perfusion measurements allowed longitudinal monitoring of hypoxia and vascular function changes in the same animals, after PDT. C-PDT induced parallel changes in tumor pO2 and blood flow, i.e., an initial decrease immediately after treatment, followed by a slow increase. In contrast, V-PDT led to a strong and persistent depletion of pO2, although the microcirculatory blood flow increased. Strong hypoxia after V-PDT led to a slight increase in VEGF level 24 h after treatment. C-PDT caused a ca. 5-day delay in tumor growth, whereas V-PDT was much more efficient and led to tumor growth inhibition in 90% of animals. The tumors of 44% of mice treated with V-PDT regressed completely and did not reappear for over 1 year. In conclusion, mild and transient hypoxia after C-PDT led to intense pO2 compensatory effects and modest tumor inhibition, but strong and persistent local hypoxia after V-PDT caused tumor growth inhibition. © 2014 Elsevier Inc. All rights reserved.

Pereira M.M.,University of Coimbra | Calvete M.J.F.,University of Coimbra | Carrilho R.M.B.,University of Coimbra | Abreu A.R.,University of Coimbra | Abreu A.R.,Luzitin SA
Chemical Society Reviews | Year: 2013

The development of large scale synthesis of enantiopure and thermally stable (R)- and (S)-BINOL molecules constitutes a key milestone in the field of asymmetric catalysis. Particularly, a great variety of chiral binaphthyl-based phosphorus compounds, herein represented by phosphite and phosphine classes, have earned considerable relevance due to their versatility as ligands in enantioselective metal-catalysed reactions, allowing the preparation of optically active products with the desired enantiopurity. This review highlights the most relevant concepts and accounts regarding general synthetic procedures for binaphthyl-based mono- and bidentate phosphites and phosphines. Furthermore, the search for environmentally benign chemical catalytic processes compelled us to also give special attention to the functionalisation of binaphthyl-based phosphorus ligands for use in alternative reaction media. When available, a critical selection of their applications in catalysis is briefly assessed. © 2013 The Royal Society of Chemistry.

Silva E.F.F.,University of Coimbra | Schaberle F.A.,Luzitin SA | Monteiro C.J.P.,University of Coimbra | Dabrowski J.M.,Jagiellonian University | And 2 more authors.
Photochemical and Photobiological Sciences | Year: 2013

High fluorescence quantum yields, high singlet oxygen quantum yields and intense absorptions in the phototherapeutic window are fundamental properties for compounds intended for fluorescence diagnosis and photodynamic therapy. We report on photostable chlorins that combine these properties. The fluorinated tetraphenylchlorin FCMet has ΦF = 0.396 and Φ Δ = 0.58 ± 0.07, whereas F2CMet has ΦF = 0.360 and ΦΔ = 0.54 ± 0.05, and both have molar absorption coefficients larger than 30000 M-1 cm -1 above 650 nm. These dual functional agents use nearly all the energy absorbed to perform the desired functions and are appropriate for theranostics applications. This journal is © The Royal Society of Chemistry and Owner Societies.

Dabrowski J.M.,Jagiellonian University | Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA | Pereira M.M.,University of Coimbra | And 5 more authors.
Free Radical Biology and Medicine | Year: 2012

Sulfonamides of halogenated bacteriochlorins bearing Cl or F substituents in the ortho positions of the phenyl rings have adequate properties for photodynamic therapy, including strong absorption in the near-infrared (λ max ≈ 750 nm, ε ≈ 10 5 M - 1 cm - 1), controlled photodecomposition, large cellular uptake, intracellular localization in the endoplasmic reticulum, low cytotoxicity, and high phototoxicity against A549 and S91 cells. The roles of type I and type II photochemical processes are assessed by singlet oxygen luminescence and intracellular hydroxyl radical detection. Phototoxicity of halogenated sulfonamide bacteriochlorins does not correlate with singlet oxygen quantum yields and must be mediated both by electron transfer (superoxide ion, hydroxyl radicals) and by energy transfer (singlet oxygen). The photodynamic efficacy is enhanced when cellular death is induced by both singlet oxygen and hydroxyl radicals. © 2012 Elsevier Inc.

Saavedra R.,University of Coimbra | Rocha L.B.,Luzitin SA | Dabrowski J.M.,Jagiellonian University | Arnaut L.G.,University of Coimbra | Arnaut L.G.,Luzitin SA
ChemMedChem | Year: 2014

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 lowdensity 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 mgkg1 did not elicit significant skin reactions. © 2014 Wiley-VCH Verlag GmbH and Co.

Pereira M.M.,University of Coimbra | Abreu A.R.,Luzitin SA | Goncalves N.P.F.,Luzitin SA | Calvete M.J.F.,University of Coimbra | And 6 more authors.
Green Chemistry | Year: 2012

This paper describes an environmentally sustainable synthetic method for the preparation of a set of meso-aryl hydroporphyrins, namely chlorins and bacteriochlorins, via reduction of porphyrins with diimide, in the total absence of solvents and bases. Thermomicroscopy studies clearly showed that the process is a typical solvent-free reaction. This journal is © The Royal Society of Chemistry.

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