Class of 2009 Abstract / OBJECTIVES: The primary objective of this experiment was to characterize the pH stability range of 20% Pluronic lecithin organogel (PLO). We intended to determine the viscosity at varying pHs. We prepared six samples of 20% PLO. METHODS: An initial rheological reading of each sample was recorded by a dynamic stress rheometer. Each sample was titrated drop-wise with citric acid or KOH in 0.5 pH increments. When the desired pH was obtained, a 0.5 mL sample was analyzed with a dynamic stress rheometer, RS-200, using Rheos software. RESULTS: Since PLO is a non-Newtonian substance, viscosity changed relative to shear stress and we were not able to examine a correlation of pH with viscosity. Instead we inputted the data into Microsoft Excel® and plotted a shear stress versus viscosity curve for each sample to identify trends. CONCLUSIONS: We were unable to achieve our primary objective of determining the viscosity characterization of 20% PLO at varying pHs due to the non-Newtonian nature of the material. Subjectively, we determined the viscosity of 20% PLO is not substantially affected by pH. Other factors such as temperature, excess liquid, and surfactant ability may influence viscosity and need to be examined in the future.

A Terapia Fotodinâmica (TFD) contra o melanoma cutâneo tem encontrado várias limitações devido à interferência de cromóforos endógenos (melanina) na irradiação deste tipo de cancêr de pele. Agentes fotossensibilizantes que absorverem em comprimentos de onda superiores a 650 nm evitam a competição com a melanina (absorção máxima 530 nm). Neste cenário, surge a ftalocianina de cloroalumínio com forte absorção entre 670-680 nm. Entretanto, esta molécula é lipofílica, o que impede sua aplicação na terapêutica. Para superar este problema, esforços têm sido direcionados para o desenvolvimento de sistemas de veiculação de fármacos hidrofóbicos. Portanto, o objetivo deste trabalho foi desenvolver, caracterizar e avaliar o efeito fotodinâmico de ClAlPc encapsulada em nanocápsulas e nanopartículas de organogel. As nanocápsulas contendo ClAlPc foram obtidas pelo método de nanoprecipitação por meio de um planejamento fatorial 23 e as nanopartículas de organogel contendo ClAlPc foram preparadas pela dispersão a quente do organogel em solução aquosa. Ambas as formulações coloidais foram caracterizadas com relação ao diâmetro médio, índice de polidispersão (IPd), potencial zeta, eficiência de encapsulação (E.E.) e estabilidade física. Os ensaios in vitro de toxicidade e fotocitotoxicidade de ClAlPc nanoencapsulada e/ou livre foram realizados sobre as linhagens melanocíticas WM1552C, WM278, WM1617 e B16-F10. O método de nanoprecipitação foi capaz de produzir nanocápsulas em tamanho nanométrico (233,0 nm ±2,00), com uma distribuição de tamanho homogênea e monodispersa (0,309 ±0,0038), bem como potencial zeta significantemente negativo de 29,6 mV (±3,91). A formulação de nanocápsulas apresentou uma boa E.E. de 63,7% para a ClAlPc. O conteúdo de ClAlPc presente nas formulações de nanocápsulas foi determinado pelos métodos analíticos espectrofotométrico e espectrofluorimétrico validados, os quais foram capazes de quantificar a ClAlPc com precisão e exatidão. O estudo de estabilidade física das formulações de nanocápsulas revelou o caráter estável desta formulação por um período de até 12 meses. As nanopartículas de organogel contendo ClAlPc apresentaram diâmetro médio de 282,7 nm (±2,99), IPd de 0,343 (±0,0280) e potencial de superfície de + 49,3 mV (±1,84). A formulação de nanopartículas de organogel apresentou uma E.E.de ClAlPc de 60%. O estudo de estabilidade física também revelou um comportamento estável das nanopartículas de organogel por um período de 6 meses. Os estudos de toxicidade na ausência de luz demonstraram o caráter biocompatível das nanocápsulas desenvolvidas e foi possível comprovar o excelente efeito fototóxico da ClAlPc nanoencapsulada sobre todas as linhagens melanocíticas com combinação de 0,30 µg.mL-1 de ClAlPc nanoencapsulada e doses de luz de 150 ou 500 mJ.cm-2, nestas condições a fração de morte celular foi superior a 90%. Portanto, estes resultados confirmam o potencial de nanocarreadores contendo ClAlPc como sistema de veiculação de compostos hidrofóbicos aplicados à TFD. / Photodynamic Therapy (PDT) against melanoma has found several limitations due to interference from endogenous chromophores (melanin) in the irradiation of this skin cancer. Photosensitizer agents which absorb at wavelengths above 650 nm may avoid melanin competition. In this context, the chloroaluminum phthalocyanine is a promissor photosensitizer with strong absorption between 670-680 nm. However, this molecule is lipophilic difficulting its application in therapy. In order to overcome such problem, efforts have focused on development of drug delivery systems containing hydrophobic photosensitizers. Therefore, the aim of this study was to develop, characterize, and evaluate the photodynamic effect of ClAlPc encapsulated into nanocapsules and organogel nanoparticles. The nanocapsules containing ClAlPc were obtained by nanoprecipitation method using a factorial design 23, and organogel nanoparticles containing ClAlPc were prepared hot dispersion of organogel in aqueous solution. Both colloidal formulations were characterized with respect to average diameter, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE), and physical stability. The in vitro tests for toxicity and photocytotoxicity of nanoencapsulated and free ClAlPc were performed on melanocytic cell lines (WM1552C, WM278, WM1617, and B16-F10). The nanoprecipitation method was able to produce nanocapsules with nanometer-size (233.0 nm ± 2.00), PdI of 0.309 (± 0.0038) indicating homogeneous and monodisperse formulations, as well as significantly negative zeta potential of 29.6 mV (± 3.91). The formulation of nanocapsules showed a good EE of 63.7% for ClAlPc. The ClAlPc content present in nanocapsules was determined by validated analytical spectrophotometric and spectrofluorimetric methods, which were reliably able to determine ClAlPc in nanocapsules. The study of physical stability for nanocapsules showed the stable character of this formulation for a period of 12 months. The nanoparticles of organogel containing ClAlPc had an average diameter of 282.7 nm (± 2.99), IPD of 0.343 (± 0.0280), and surface potential of + 49.3 mV (± 1.84). The formulation of organogel nanoparticles showed a ClAlPc EE of 60%. The physical stability study also revealed a behavior stable organogel nanoparticles for a period of 6 months. Toxicity studies in darkness conditions have been confirmed biocompatibility of nanocapsules. Besides that, the excellent photodynamic effect of ClAlPc nanoencapsulated was reached on all melanocytic cell lines using an arrangement of 0.30 g.mL-1 of ClAlPc encapsulated, and light doses of 150 or 500 mJ.cm-2, under these conditions the cell death fraction was more than 90%. Therefore, these results confirm the potential of nanocarriers containing ClAlPc as delivery system for hydrophobic photosensitizers applied to PDT.

A Terapia Fotodinâmica (TFD) contra o melanoma cutâneo tem encontrado várias limitações devido à interferência de cromóforos endógenos (melanina) na irradiação deste tipo de cancêr de pele. Agentes fotossensibilizantes que absorverem em comprimentos de onda superiores a 650 nm evitam a competição com a melanina (absorção máxima 530 nm). Neste cenário, surge a ftalocianina de cloroalumínio com forte absorção entre 670-680 nm. Entretanto, esta molécula é lipofílica, o que impede sua aplicação na terapêutica. Para superar este problema, esforços têm sido direcionados para o desenvolvimento de sistemas de veiculação de fármacos hidrofóbicos. Portanto, o objetivo deste trabalho foi desenvolver, caracterizar e avaliar o efeito fotodinâmico de ClAlPc encapsulada em nanocápsulas e nanopartículas de organogel. As nanocápsulas contendo ClAlPc foram obtidas pelo método de nanoprecipitação por meio de um planejamento fatorial 23 e as nanopartículas de organogel contendo ClAlPc foram preparadas pela dispersão a quente do organogel em solução aquosa. Ambas as formulações coloidais foram caracterizadas com relação ao diâmetro médio, índice de polidispersão (IPd), potencial zeta, eficiência de encapsulação (E.E.) e estabilidade física. Os ensaios in vitro de toxicidade e fotocitotoxicidade de ClAlPc nanoencapsulada e/ou livre foram realizados sobre as linhagens melanocíticas WM1552C, WM278, WM1617 e B16-F10. O método de nanoprecipitação foi capaz de produzir nanocápsulas em tamanho nanométrico (233,0 nm ±2,00), com uma distribuição de tamanho homogênea e monodispersa (0,309 ±0,0038), bem como potencial zeta significantemente negativo de 29,6 mV (±3,91). A formulação de nanocápsulas apresentou uma boa E.E. de 63,7% para a ClAlPc. O conteúdo de ClAlPc presente nas formulações de nanocápsulas foi determinado pelos métodos analíticos espectrofotométrico e espectrofluorimétrico validados, os quais foram capazes de quantificar a ClAlPc com precisão e exatidão. O estudo de estabilidade física das formulações de nanocápsulas revelou o caráter estável desta formulação por um período de até 12 meses. As nanopartículas de organogel contendo ClAlPc apresentaram diâmetro médio de 282,7 nm (±2,99), IPd de 0,343 (±0,0280) e potencial de superfície de + 49,3 mV (±1,84). A formulação de nanopartículas de organogel apresentou uma E.E.de ClAlPc de 60%. O estudo de estabilidade física também revelou um comportamento estável das nanopartículas de organogel por um período de 6 meses. Os estudos de toxicidade na ausência de luz demonstraram o caráter biocompatível das nanocápsulas desenvolvidas e foi possível comprovar o excelente efeito fototóxico da ClAlPc nanoencapsulada sobre todas as linhagens melanocíticas com combinação de 0,30 µg.mL-1 de ClAlPc nanoencapsulada e doses de luz de 150 ou 500 mJ.cm-2, nestas condições a fração de morte celular foi superior a 90%. Portanto, estes resultados confirmam o potencial de nanocarreadores contendo ClAlPc como sistema de veiculação de compostos hidrofóbicos aplicados à TFD. / Photodynamic Therapy (PDT) against melanoma has found several limitations due to interference from endogenous chromophores (melanin) in the irradiation of this skin cancer. Photosensitizer agents which absorb at wavelengths above 650 nm may avoid melanin competition. In this context, the chloroaluminum phthalocyanine is a promissor photosensitizer with strong absorption between 670-680 nm. However, this molecule is lipophilic difficulting its application in therapy. In order to overcome such problem, efforts have focused on development of drug delivery systems containing hydrophobic photosensitizers. Therefore, the aim of this study was to develop, characterize, and evaluate the photodynamic effect of ClAlPc encapsulated into nanocapsules and organogel nanoparticles. The nanocapsules containing ClAlPc were obtained by nanoprecipitation method using a factorial design 23, and organogel nanoparticles containing ClAlPc were prepared hot dispersion of organogel in aqueous solution. Both colloidal formulations were characterized with respect to average diameter, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE), and physical stability. The in vitro tests for toxicity and photocytotoxicity of nanoencapsulated and free ClAlPc were performed on melanocytic cell lines (WM1552C, WM278, WM1617, and B16-F10). The nanoprecipitation method was able to produce nanocapsules with nanometer-size (233.0 nm ± 2.00), PdI of 0.309 (± 0.0038) indicating homogeneous and monodisperse formulations, as well as significantly negative zeta potential of 29.6 mV (± 3.91). The formulation of nanocapsules showed a good EE of 63.7% for ClAlPc. The ClAlPc content present in nanocapsules was determined by validated analytical spectrophotometric and spectrofluorimetric methods, which were reliably able to determine ClAlPc in nanocapsules. The study of physical stability for nanocapsules showed the stable character of this formulation for a period of 12 months. The nanoparticles of organogel containing ClAlPc had an average diameter of 282.7 nm (± 2.99), IPD of 0.343 (± 0.0280), and surface potential of + 49.3 mV (± 1.84). The formulation of organogel nanoparticles showed a ClAlPc EE of 60%. The physical stability study also revealed a behavior stable organogel nanoparticles for a period of 6 months. Toxicity studies in darkness conditions have been confirmed biocompatibility of nanocapsules. Besides that, the excellent photodynamic effect of ClAlPc nanoencapsulated was reached on all melanocytic cell lines using an arrangement of 0.30 g.mL-1 of ClAlPc encapsulated, and light doses of 150 or 500 mJ.cm-2, under these conditions the cell death fraction was more than 90%. Therefore, these results confirm the potential of nanocarriers containing ClAlPc as delivery system for hydrophobic photosensitizers applied to PDT.

Ce travail de thèse a pour objet l’étude d’organogélifiants bis(urée) originaux de faible masse moléculaire (LMWG), intégrant ou non des unités fluorescentes pyrènes. Il intègre les aspects liés à la synthèse organique de ces systèmes, l’étude de leur capacité de gélification pour des solvants variés, la caractérisation des édifices auto-assemblés correspondants -en particulier à l’aide de méthodes spectroscopiques et de microscopies variées-, et enfin la mise en œuvre d’une méthode originale de structuration par alignement des fibres auto-assemblées. Deux premiers organogélifiants bis(urée) modèles ont été synthétisés et leur aptitude à geler de multiples solvants ainsi que la structuration des auto-assemblages correspondant ont été étudiées en détail (RMN, microscopies optiques et électroniques). L’étude de l’alignement des fibres résultantes a été réalisée avec succès en utilisant un gabarit, par remplissage des pores d’une membrane d’alumine, puis dissolution de cette dernière. Une seconde série d’organogélifiants bis(urée), intégrant cette fois une, deux ou encore trois unités fluorescentes pyrène a été synthétisée. L’intégration covalente de cette unité dans nos gels s’est révélée intéressante à plusieurs titres. D’abord, celle-ci joue le rôle de sonde interne permettant une caractérisation approfondie de la structuration des édifices auto-assemblés à l’aide des spectroscopies d’absorption et d’émission en fonction de la température. Cette unité participe par ailleurs à la robustesse des objets nanostructurés, comme remarquablement mis en évidence dans les gels hybrides associant les gélifiants tris(pyrényles) de symétrie C3, soit à un gélifiant porteur de deux unités pyrène ou soit à un dérivé accepteur-π d’électrons, introduit dans le milieu. / This thesis focuses on the study of original bis(urea) low molecular weight organogelators (LMWG), integrating or not fluorescent pyrene units. This study integrates organic synthesis of these systems, study of their gelling capacity for various solvents, characterization of the corresponding self-assembled structures through various spectroscopic and microscopy techniques, and finally implementation of an original structuring method by alignment of the self-assembled fibers. Two first model bis(urea) organogelators were synthesized and their ability to gel multiple solvents as well as the structuration of the corresponding self-assemblies have been studied in detail (NMR, optical and electron microscopy). Alignment of the resulting fibers has been successfully performed using a template method, by filling the pores of an alumina membrane, followed by dissolution of the latter. A second series of bis(urea) organogelators, which incorporate one, two or three pyrene fluorescent units was synthesized. The integration of this unit in our gels has proved useful in several ways. First, it acts as an internal probe for further characterize the resulting self-assembled structures, using variable temperature absorption and emission spectroscopies. The pyrene unit also contributes to the robustness of the nanostructured objects, as remarkably evidenced in hybrid gels involving tris(pyrenyl) C3 symmetry gelators associated to either a bis(pyrenyl) gelator or to a π-acceptor derivative.

Ce travail décrit la synthèse et l’étude structurale d’oligomères mixtes et de leurs analogues cycliques alternant des résidus acides α aminés et des résidus acides azaaminés. Le premier chapitre concerne la synthèse en solution des 1:1-[α/aza]-oligomères et des 2:1 [α/aza] oligomères obtenus respectivement par oligomérisation par couplage peptidique de l’azadipeptide Boc-azaPhe-Ala-OMe et de l’azatripeptide Boc-Phe-azaPhe-Ala-OMe correctement déprotégés. Pour la première famille en série L, les rendements en dimérisation et en trimérisation sont moyens en raison de la faible nucléophilie du partenaire amine azadipeptidique. Quant aux 2:1 [α/aza]-oligomères de taille variable, ils ont été isolés avec de très bons rendements quelle que soit la nature L et/ou D des résidus acides α aminés de l’azatripeptide. Ce chapitre présente également l’étude conformationnelle de ces oligomères par spectroscopies RMN et IR, par modélisation moléculaire ainsi que dans certains cas par diffraction des RX. L’analyse des 1:1 [α/aza] oligomères a révélé une auto-structuration majoritaire en solution alternant un coude β et un coude γ stabilisés par des liaisons hydrogène intramoléculaires. L’examen des 2:1 [α/aza] oligomères a permis de mettre en évidence, en série homochirale (L), une conformation majoritaire caractérisée par la formation de coudes β stabilisés par un réseau de liaisons hydrogène intramoléculaires. Des repliements, induits par la formation de coudes β et de coudes γ s’imposent en série hétérochirale (DLDL…). Le second chapitre est consacré à la synthèse en solution et à l’étude conformationnelle des analogues cycliques des oligomères présentés dans le premier chapitre. Les 2:1 [α/aza] cyclooligomères sont surtout discutés, leur synthèse par couplage peptidique intramoléculaire étant plus efficace que celle des 1:1-[α/aza]-cyclooligomères. La formation de nanotubes due à l’empilement des 2 :1-[α/aza]-cyclohexamères homochiraux (L) a été mise en évidence à l’état solide par établissement de liaisons hydrogène intermoléculaires puis suggérée en solution. Le pouvoir gélifiant de certains solvants organiques de l’analogue hétérochiral (DLDL) présage également de son auto-structuration en nanotubes discutée uniquement en solution faute de structure à l’état solide / This work describes the synthesis and structural analysis of mixed oligomers and their cyclic analogues containing an alternation of α-acid residues and α-azaamino acids moieties. The first chapter deals with the “in solution” synthesis of 1:1-[α/aza]-oligomers and 2:1 [α/aza] oligomers respectively, obtained by oligomerization of the properly deprotected azadipeptide Boc-Ala-azaPhe-OMe azadipeptide and Boc-Phe-Ala-OMe-azaPhe tripeptide. For the first family series with L aminoacids, yields dimerization and trimerization are moderate due to the low nucleophilicity of the amine azadipeptidic partner. Concerning the 2:1-[α/aza]-oligomers of variable sizes, they were isolated with very good yields whatever the nature L and / or D of the α-aminoacid residues of the azatripeptide. This chapter also presents the conformational study of these oligomers by NMR and IR spectroscopy, molecular modeling and in some cases by X-ray diffraction. Analysis of the 1:1 [α/aza] oligomers reveals mainly an self-assembly in solution with alternation of β- and γ-turns stabilized by intramolecular hydrogen bonds. Examination of the 2:1 [α/aza] oligomers in homochiral series (L) evidenced a main conformation with repetitive β turns. Regarding the heterochiral series (DLDL….), it is an alternation of β- and γ-turns which is observed. The second chapter is devoted to the solution synthesis in solution and conformational study of cyclic analogues oligomers presented in the first chapter. 2: 1-[α/aza]-cyclooligomers are mostly discussed because their synthesis by intramolecular peptide coupling is more effective than the 1:1 [α/aza]-cyclooligomers. The formation of nanotubes due to the stacking of the homochiral (L) 2:1-[α/aza]-cyclohexamers has been shown in the solid state and suggested in solution. Furthermore, in heterochiral series, the gelling properties of some organic solvents suggest a self-assembly in solution

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The objective of this study was to investigate the potential application of rice bran wax (RBW) organogel to replace solid fat content and create the fat network in ice cream. Ice creams with 10% fat or 15% fat were formulated with RBW organogel as the fat source, and two different emulsifiers were used: polmo, a commercial blend of emulsifiers which contains 80% mono- and diglycerides and 20% polysorbate 80, and Glycerol monooleate (GMO). Candelilla wax (CDW) organogel and carnauba wax (CBW) organogel were also tested for comparison. RBW organogel had the ability to form and sustain structure in 15% fat ice creams when GMO was used as the emulsifier. Transmission electron microscopy revealed that the RBW crystal morphology within the fat droplet, when GMO was used as the emulsifier, was characterized by the growth of crystals at the outer edge of the droplet which increased fat destabilization and network formation. / Nestlé Product Technology Centre, France

No description available.

Une nouvelle plateforme hydrogel uniquement formée par l’association de nanocapsules lipidiques (NCLs) a été développée en s’inspirant de précédents travaux utilisant une gemcitabine modifiée. Afin de limiter la toxicité de l’hydrogel, la gemcitabine a été remplacée par la cytidine, rendue amphiphile par une chaîne aliphatique (Cyt-C16). Placée à l’interface huile/eau des NCLs, la Cyt-C16 permet la formation d’un réseau tridimensionnel de NCLs à l’origine de la gélification. Un plan de mélange a permis d’optimiser les procédés de formulation de 4 tailles de NCLs modèles. Les propriétés viscoélastiques des hydrogels sont modulables. Plus les concentrations en NCLs et Cyt-C16 sont élevées, plus le gel est « rigide », indépendamment de la taille des NCLs qui doit être supérieure à 50 nm pour permettre la gélification. Les hydrogels sont injectables et permettent une libération prolongée de NCLs (de taille mono-disperse), sans toxicité supplémentaire in vitro, du fait de la présence de la Cyt-C16. De plus, uniquement solubilisée dans l’huile,la Cyt-C16 permet d’obtenir un organogel, dont les propriétés viscoélastiques sont renforcées en augmentant sa concentration. L’injection sous-cutanée (SC) in vivo des deux gels est bien tolérée et entraine une réaction inflammatoire locale comparable à celle provoquée par un excipient pharmaceutiquement acceptable. Ces deux formes pourront être utilisées pour libérer de façon prolongée différents actifs. Deux applications précliniques des hydrogels ont été explorées, l’une utilisant la voie SC pour cibler les ganglions lymphatiques, la seconde permettant un traitement local des suites opératoires d’une résection de glioblastome. / An innovative hydrogel platform obtained by the association of lipid nanocapsules (LNCs) was based on the previous work on modified gemcitabine. To limit the inherent toxicity of the hydrogel, gemcitabine was replaced by cytidine, then modified by an aliphatic chain (Cyt-C16). The hydrogel network was allowed by H-bond interactions between cytidine moieties exposed at the oil/water interfaces of LNCs. An experimental plan provided the formulation processes for 4 optimized sizes of model LNCs. The gelation was only possible for LNC sizes higher than 50 nm, and the hydrogel viscoelastic properties are versatile. The hydrogel is more “rigid” when LNC and Cyt-C16 concentrations increase, independently of the LNC size. The hydrogels are injectable and allow a sustained release of LNCs (withmonodisperse size), without additional in vitrocytotoxicity due to Cyt-C16. Moreover, when solubilized in oil, Cyt-C16 alone produced an organogel platform, whose viscoelastic properties are strengthened increasing its concentration. Both types of gels showed a good biocompatibility after an in vivo subcutaneous (SC) injection, with a local inflammatory response similar to that of induced by an approved excipient. These two forms could be used to sustain the release of various drugs, and two preclinical applications of hydrogels have been explored : one using the SC route to target lymph nodes, and the second for local treatment after glioblastoma resection.