Orientador: Jean Leandro dos Santos / Coorientador: Marcos Antonio Corrêa / Banca: José Ricardo Soares de Oliveira / Banca: Isabele Rodrigues Nascimento / Banca: Vera Lucia Borges Isaac / Banca: Chung Man Chin / Resumo: O desenvolvimento do câncer de pele e o fotoenvelhecimento estão diretamente associados à exposição dos indivíduos à radiação ultravioleta (UV) de modo excessivo e sem a proteção adequada. Os filtros solares são conhecidamente capazes de proteger a pele contra os efeitos nocivos dessa radiação. Apesar disso, os filtros solares ainda apresentam limitações justificando a pesquisa de substâncias mais efetivas e seguras. Este trabalho teve como objetivo o planejamento, a síntese e a avaliação de novos filtros com capacidade ampliada de proteção contra as radiações UVA e UVB, associado a propriedades antioxidantes, obtidos através da estratégia de triplicação molecular tendo como protótipo as moléculas do resveratrol e ethylhexyl triazone. Foram sintetizados, isolados e caracterizados oito substâncias inéditas (FSN-1 a FSN-8). Todas as substâncias fundiram em temperaturas acima de 218°C, significativamente superior ao padrão ethylhexyl triazone (119,99°C), sendo FSN-2 e FSN-7 as substâncias que apresentaram menor e maior temperatura de decomposição, respectivamente (FSN-2: 236,25°C; FSN-7: 326,22°C). Todas as substâncias apresentaram atividade antioxidante, sendo a substância FSN-8 a mais ativa em relação às demais substâncias sintetizadas e aos padrões de resveratrol e ethylhexyl triazone. Embora todas as substâncias tenham comprimento de onda máximo na região espectral UVB, os resultados obtidos no ensaio in vitro de atividade fotoprotetora demonstraram capacidade protetora tamb... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The development of skin cancer and photoaging are directly associated with exposure to ultraviolet (UV) radiation without adequate protection. Sunscreens are known to be able to protect the skin against the harmful effects of such radiation. Despite this, sunscreen still exhibits limitations justifying the research for more effective and safe compounds. The aim of this work was design, synthesize and evaluate new sunscreens possessing wide protection against UVA and UVB, associated with antioxidant properties, obtained through molecular triplication strategy, using resveratrol and ethylhexyl triazone as prototype molecules. Eight novel substances (FSN-1 - FSN-8) were synthesized, isolated and characterized. All synthesized substances melted at temperatures above 218°C, significantly higher than ethylhexyl triazone (119.99°C). FSN-2 and FSN-7 presented, respectively, the lowest and the highest decomposition temperatures (FSN-2: 236,25°C; FSN-7: 326,22°C). All synthesized substances have exhibited antioxidant effect and FSN-8 has exhibited antioxidant effect superior than resveratrol, ethylhexyl triazone and the other substances. All synthesized substances exhibited maximum wavelength at UVB spectral region, and they also showed a protective activity against UVA radiation in photoprotection in vitro assay. FSN-3 was the most active susncreen (SPF 17; UVAPF 13). FSN-7 (SPF 14, UVAPF 7) and FSN-1 (SPF 9; UVAPF 5) also should be highlighted, presenting more photoprotection ability than resveratrol (SPF 2 and UVAPF 2) and ethylhexyltriazone (SPF 3 and UVAPF 3). All these results allowed the identification of new sunscreens with wide spectra against UV radiation useful to prevent skin cancer and photoaging. / Doutor

Orientador: Leila Aparecida Chiavacci / Coorientadora: Renata Cristina Kiatkoski Kaminski / Banca: Marco Antonio Correa / Banca: Marian Rosaly Davolos / Resumo: A incidência de câncer de pele em todo o mundo cresce exponencialmente principalmente devido à exposição freqüente à radiação ultravioleta (UV). O uso de protetor solar é a medida mais eficaz para a sua prevenção. O dióxido de titânio (TiO2) é um filtro inorgânico que atua espalhando, refletindo e absorvendo a radiação UV, é fotoestável, hipoalergênico, entretanto, deixa a pele com aspecto esbranquiçado dependendo do tamanho da partícula. Hoje em dia há uma procura grande por produtos multifuncionais e o uso de estruturas líquido-cristalinas vem crescendo cada vez mais por promover a liberação controlada de ativos. O objetivo deste trabalho foi desenvolver sistemas multifuncionais líquido-cristalinos contendo nanopartículas de TiO2 transparentes capazes de agir como fotoprotetores e de liberar terpinem-4-ol (terpeno com atividade antioxidante) de forma controlada prevenindo e/ou tratando o câncer de pele. O teste de citotoxicidade mostrou que as nanopartículas de TiO2 obtidas através do processo sol-gel não foram citotóxicas para as duas linhagens de células testadas (queratinócitos de pele humana - HaCaT e fibroblastos de pulmão humano - MRC-5), evidenciando o uso deste material nos humanos sem causar danos. O potencial zeta das nanopartículas indicou que entre pH 5 e 7, que não é agressivo para pele humana, é possível evitar aglomeração das nanopartículas por estas apresentarem cargas superficiais significativas. Os dados de espalhamento de raios X a baixo ângulo e microscopia de luz polarizada mostraram que foi possível manter a estrutura líquido-cristalina das formulações com a presença de nanopartículas de TiO2 e terpinem-4-ol. O teste de liberação in vitro das formulações contendo 1 e 5% de terpinem-4-ol mostraram que o sistema líquido-cristalino controlou... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The incidence of skin cancer growth exponentially in all the world mainly due to the frequent ultraviolet (UV) radiation exposition. The sunscreen use is one of the efficient manners to prevent the skin cancer. The titanium dioxide (TiO2) is an inorganic filter which works scattering, reflecting and absorbing the UV radiation, it is photostable, hypoalergenic, but it presents a whiteness appearance depending on the particle size. Nowadays there is a high demand for multifunctional products and the use of liquid crystal has been increasing because it promotes active controlled delivery. The propose of this work is to develop liquid crystalline multifunctional systems with transparent TiO2 nanoparticles able to photoprotect the skin and release in a controlled manner terpinem-4-ol (a terpen with antioxidant activity) to prevent and/or treat the skin cancer. The citotoxicity assay showed that TiO2 nanoparticles obtained by sol-gel process weren't cytotoxics to the two cell lines tested (human skin keratinocites - HaCaT and human lung fibroblasts - MRC-5), evidencing the use of this material on the humans without dangers. The nanoparticles zeta potential indicated that at pH about 5 and 7, pH that is not irritative to the human skin, it's possible to prevent nanoparticles aggregation due to their significative superficial charges. The small angle scattering X rays and light polarized microscopy data showed that it is possible to maintain the liquid crystalline structure of the formulations with the presence of TiO2 nanoparticles and terpinem-4-ol. The in vitro terpinem-4-ol release assay of the formulations containing 1 and 5% of terpinem-4-ol showed the controlled release of the liquid crystalline systems (liberation at about 13% in 12 hours), being zero order the best mathematical model that fit the release profile, indicating... (Complete abstract click electronic access below) / Mestre

Orientador : Jean Leandro dos Santos / Coorientador: Marcos Antonio Corrêa / Banca: Chung Man Chin / Banca: Gustavo Henrique Goulart Trossini / Resumo: A exposição à radiação ultravioleta (UV) é um dos principais fatores que contribuem para o desenvolvimento de câncer de pele e fotoenvelhecimento. Este trabalho teve como objetivo a obtenção de novos filtros solares com capacidade ampliada de proteção contra radiação UVA e UVB associada a propriedades antioxidantes, obtidos através da estratégia de hibridação molecular, entre filtros existentes (avobenzona e metoxicinamato de octila) e produtos naturais (resveratrol e ácido ferúlico). Foram sintetizados, isolados e caracterizados oito compostos inéditos obtidos através de hibridação molecular: (E)-4-hidroxi-N'-(4-hidroxibenzilideno)benzidrazida (molécula I), (E)-N'-(3,5-diidroxibenzilideno)-4-hidroxibenzidrazida (molécula II), (E)-4-(terc-butil)-N'-(3,5-diidroxibenzilideno)benzidrazida (molécula III), (E)-4-(terc-butil)-N'-(4-hidroxibenzilideno)benzidrazida (molécula IV), (E)-4-hidroxi-N'-((E)-3-(4-metoxifenil)alilideno)benzidrazida (molécula V), (E)-4-(terc-butil)-N'-((E)-3-(4-metoxifenil)alilideno)benzidrazida (molécula VI), (E)-4-hidroxi-N'-((E)-3-(4-hidroxi-3-metoxifenil)alilideno)benzidrazida (molécula VII) e (E)-4-(terc-butil)-N'-((E)-3-(4-hidroxi-3-metoxifenil)alilideno)benzidrazida (molécula VIII). O composto VIII apresentou-se como o mais termoestável, decompondo-se acima de 295°C. Na avaliação da atividade antioxidante, os compostos I, IV, VII e VIII apresentaram maior atividade, sendo os compostos VII e VIII semelhantes aos padrões ácido ferúlico, t-resveratrol e ácido ascórbico. Os resultados obtidos no ensaio de atividade fotoprotetora demonstraram capacidade protetora contra radiação UVA para os compostos I, IV, V, VI, VII e VIII, sendo todos comparáveis ao padrão t-resveratrol. O composto VI apresentou-se como o mais ativo quanto à capacidade fotoprotetora UVA sendo, inclusive, superior ao padrão t-resveratrol. Os compostos II e III foram classificados como potenciais filtros UVB e ... / Abstract: The exposure to ultraviolet radiation is the mainly factor to develop skin cancer and photoaging. This work aimed to obtain new sunscreens with enhance abilities to protect against UVA and UVB radiation associated to antioxidant properties, obtained by molecular hybridization strategy among existing filters (avobenzone and methoxycinnamate) and natural products (resveratrol and ferulic acid). Eight new compounds were synthesized, isolated and characterized by molecular hybridization: (E)-4-hydroxy-N'-(4-hydroxybenzylidene)benzohydrazide (molécula I), (E)-N'-(3,5-dihydroxybenzylidene)-4-hydroxybenzohydrazide (molécula II), (E)-4-(tert-butyl)-N'-(3,5-dihydroxybenzylidene)benzohydrazide (molécula III), (E)-4-(tert-butyl)-N'-(4-hydroxybenzylidene)benzohydrazide (molécula IV), (E)-4-hydroxy-N'-((E)-3-(4-methoxyphenyl)allylidene)benzohydrazide (molécula V), (E)-4-(tert-butyl)-N'-((E)-3-(4-methoxyphenyl)allylidene)benzohydrazide (molécula VI), (E)-4-hydroxy-N'-((E)-3-(4-hydroxy-3-methoxyphenyl)allylidene)benzohydrazide (molécula VII) and (E)-4-(tert-butyl)-N'-((E)-3-(4-hydroxy-3-methoxyphenyl)allylidene)benzohydrazide (molécula VIII). Compound VIII was presented as the most thermostable, showing decomposition temperature above 295°C. Compounds I, IV, VII and VIII presented more antioxidant activity than the other compounds analysed. The compounds VII and VIII were similar to ferulic acid, t-resveratrol and ascorbic acid. Compounds I, IV, V, VI, VII and VIII had abilities to protect against UVA radiation, and all of these products were similar to t-resveratrol pattern. The VI molecule had the highest photoprotection activity against UVA radiation, and it was more effective than t-resveratrol pattern. The II and III compounds were classified as UVB filters and they were more effectiveness than t-resveratrol. Compounds I, III, V and VII showed inhibitory ability for the enzyme tyrosinase, respectively, ... / Mestre

In recent years, new classes of aquatic pollutants have received growing concerns from the environmentalists due to their unclear effects and increasing release into the water environment. Generally, before entering the aquatic ecosystem, many of these emerging contaminants are deemed safe active ingredients in the commercial products. This may lead to the underestimation of their potential impacts to the environment, once these substances were drained into the natural waters. So far, a wide range of emerging contaminants are still not well studied. In this thesis work, the environmental behaviors for two typical groups of emerging contaminants, which are frequently used in personal care products, are systematically probed in the aquatic ecosystem. One is the hydrophilic compounds - artificial sweeteners and the other one is the moderate hydrophobic compounds - ultraviolet (UV) filters. Acesulfame and sucralose are two of the most commonly used artificial sweeteners, which are a newly recognized class of emerging contaminants due to their widespread occurrence and extreme persistence in water environment. To date, however, their environmental behaviors, fates as well as long term ecotoxicological contributions in our water resources still remain largely unknown. In this work, a photodegradation investigation with UV/TiO2 was performed on these two artificial sweeteners, which projected their potential impacts under prolonged exposure to intensive solar irradiation. Real-time observation of the degradation profiles in both sweeteners illustrated that formation of new photo by-products under prolonged UV irradiation is highly viable. For the first time, acute toxicity for the degradates of these two sweeteners were measured and the enhancement in their ecotoxicity has been observed during the irradiation. In an attempt to neutralize this prolonged environmental threat, the feasibility of UV/TiO2 as an effective mineralization process in wastewater treatment was evaluated for both sweeteners. As a result, relatively higher removal efficiencies for acesulfame and sucralose were achieved in this study. For UV filters, a comprehensive investigation on their environmental behaviors and impacts was described in this thesis, covering the occurrence study in surface water and biota, environmental fate and their ecological risks. In the first step, an analytical method based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of twelve UV filters in the environmental waters, which achieved good sensitivity to sub-ng/L levels. To monitoring their occurrence in local marine environment, the regional distribution of these sunscreen compounds was monitored along the coastline of Hong Kong. At the same time, considering the intensive consumption of sunscreen products in hot weathers, seasonal variation of UV filters between summer and winter was taken into consideration in our occurrence study. Additionally, we also monitored their occurrence in the drinking water supply system of Hong Kong, including the source water in Dongjiang, raw water in local reservoirs and tap water collected from urban communities, to support a good management on the reliable water supply. Furthermore, the distribution results indicated that the incomplete removal of UV filters in the effluents could be a major source for their release into the environmental waters. Aiming to achieve the complete removal of such compounds, a powerful technique of ozonation was employed in this study and the preliminary operational conditions were further provided. Secondly, in order to gain a better understanding of their environmental fate in surface water, a simulative catalytic photodegradation study with UV/TiO2 were performed to investigate the photostability, phototoxicity and the transformation pathways of seven selected UV filters. During the photodegradation, several transformation products were primarily identified. Thirdly, since lipophilic sunscreens were easily accumulated in the biota, we also made efforts to monitor their occurrence in marine organisms of different species, including farmed fish, wild mussels, prawns and sea urchin, which were collected from local offshore areas. Last but not the least, according to the measured concentrations of UV filters in Hong Kong marine environment, we further performed the ecological risk assessment with the approach specific to the marine aquatic compartment, so as to provide the overall understanding on the environmental impacts of these UV filters.

L’exposition au soleil, et donc aux rayons ultraviolets, est de plus en plus fréquente chez l’homme dans les pays occidentaux. En effet, les modes de vie ont fortement changé ces dernières années, avec pour résultat une augmentation non négligeable des loisirs en extérieur. Ceci a pour conséquence une augmentation de l’apparition des cancers cutanés, dont le pronostic de survie est souvent mauvais et l’issue fatale. De plus, les traitements associés à ces maladies sont lourds et n’agissent pas toujours de façon efficace. Les campagnes d’information et de prévention face aux dangers du soleil restent donc les principales mesures efficaces pour lutter contre le cancer cutané lié à une surexposition au soleil. La recherche de nouveaux produits permettant de protéger de manière efficace la peau des effets néfastes des rayons UV reste donc un défi permanent et primordial pour la recherche dans l’industrie cosmétique. <p><p> Dans un premier temps, le travail a consisté à développer des nouvelles formulations de produits solaires contenant des concentrations élevées en filtres UV, conditionnées sous forme d’aérosol, celles-ci valables pour le marché européen. Une émulsion E/H et une émulsion E/Si ont donc été réalisées. Elles contenaient au final 27% de filtres UV pour l’émulsion E/H et 16,5% de filtres UV pour l’émulsion E/Si, dont 4% de filtres inorganiques pour les deux types d’émulsion. Leur viscosité était de 6800 mPa.s pour l’émulsion E/H et de 2800 mPa.s pour l’émulsion E/Si. Ces formulations étaient stables lorsqu’elles étaient conservées pendant 2 mois à 40°C et également lorsqu’elles subissaient 5 cycles de température entre 5°C et 40°C. La mise en aérosol de ces émulsions a nécessité l’utilisation de 22% de gaz propulseur (mélange :butane, propane, isobutane). <p>La taille des gouttelettes étant un paramètre important de la caractérisation des aérosols pour le choix des matériaux à utiliser ainsi que pour sécurité afin d’éviter toute inhalation pulmonaire, l’influence de différents éléments sur celle-ci a été étudiée. Nous avons ainsi montré que la concentration en gaz, la viscosité, la présence ou non de filtres inorganiques ainsi que le choix des valves et diffuseurs utilisés jouent un rôle dans la taille des gouttelettes émises, celle-ci ne pouvant pas être inférieure à 30 µm de diamètre. La taille des gouttelettes émises était supérieure à 50 µm avec pas plus de 0.1% ayant une taille inférieure à 10 µm et maximum 25% des gouttelettes ayant une taille comprise entre 10 et 30 µm. <p><p> Les produits formulés contenaient de grandes quantités en filtres solaires, organiques et inorganiques (27% pour l’émulsion E/H et 16,6% pour l’émulsion E/Si), il était donc important de vérifier qu’aucun des filtres présents dans les émulsions ne passaient à travers la peau lors de l’application des produits solaires. En effet, ceux-ci doivent rester à la surface de l’épiderme afin de maintenir l’efficacité des produits solaires et d’éviter des effets néfastes systémiques éventuels en pénétrant la peau. Une étude in vitro utilisant de la peau humaine excisée et des cellules de diffusion de Franz nous a permis de constater que les filtres inorganiques présents dans les formulations restaient en surface de la peau, et seulement deux des filtres organiques (l’EMC et MBBT) présentaient un potentiel de pénétration cutanée négligeable et non nocif pour la santé humaine (maximum 1,21 µg/ml/cm2 pour EMC et maximum 0,14 µg/ml/cm2 pour MBBT). De plus, après 24 h d’expérience, plus de 50% des filtres restaient à la surface de la peau, ce qui permettait de maintenir l’efficacité des produits solaires. Afin de mener à bien cette étude, des méthodes analytiques pour l’analyse simultanée des filtres solaires organiques d’une part, par CLHP (Chromatographie Liquide Haute Performance), et inorganiques d’autre part, par ICP-OES (Inductively Coupled Plasma - Optical Emission Spectrometry), ont été mises au point et validées. <p>Une étude in vivo non invasive, basée sur le prélèvement des couches successives du stratum corneum, a été réalisée par la suite. Cette dernière a été effectuée par la méthode du « tape stripping », qui utilise des disques adhésifs rigides, et sur 9 volontaires pendant une période de 8 h. Elle a permis de confirmer les résultats obtenus avec la méthode in vitro. Une bonne corrélation entre ces deux types d’étude a été observée. <p><p> Enfin, la dernière partie du travail a porté sur l’EMC, un des filtres organiques utilisé dans la plupart des produits solaires mis sur le marché et dans les émulsions E/H et E/Si formulées. Ce filtre présente une sensibilité à la lumière et aux rayons UV. L’encapsulation lipidique de celui-ci a donc été envisagée afin de produire des nanoparticules dont la matrice lipidique a pour but de protéger l’EMC contre une dégradation causée par les rayons UV. Trois lipides différents ont été investigués et ont montré des résultats positifs de protection vis-à-vis des rayonnements UV. En effet, après 2 h d’irradiation par les UV, une perte d’efficacité de 30% de l’EMC pur a été observée contre 10% à 21% pour l’EMC encapsulé par les différents lipides. De plus, les nanoparticules n’ont pas montré de potentiel d’augmentation de pénétration cutanée de l’EMC. <p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished