No description available.

No description available.

L'apparition d’un développement cancérigène est souvent caractéristique des tumeurs de la région de la tête et du cou. En raison des altérations prémalignes et malignes fréquentes, il n'est souvent pas possible de supprimer complètement la tumeur par chirurgie.Il en résulte un risque élevé de récidive tumorale. Par conséquent, cette recherche de doctorat vise à développer des nanoparticules photocatalytiques (NPs) qui seront utilisées localement en complément de la thérapie tumorale traditionnelle. Ces NPs, une fois absorbées par les cellules tumorales induiront la mort des cellules photocatalytiques par activation de lumière UV. Des NPs de TiO2 ayant des propriétés photocatalytiques et une taille moyenne inférieure à 20 nm étaient donc synthétisées. La biocompatibilité des NPs, leur absorption dans les cellules et un ciblage tumoral efficace devraient être garantis par une modification de surface des particules avec des molécules organiques dendritiques permettant un contrôle précis de la charge de surface des particules ainsi que la possibilité de couplage avec des anticorps. Un autre objectif était la combinaison de propriétés thérapeutiques et diagnostiques dans le système de NPs par exemple réalisé par incorporation d'agent luminescent. Cette recherche était menée à l'Université de Bordeaux (synthèse des molécules organiques pour la fonctionnalisation des particules) en coopération avec l'Institut Fraunhofer de recherche en silicate ISC à Würzburg, Allemagne (synthèse des nanoparticules). / The occurrence of field cancerization is characteristic for tumours of the head and neck region. Due to these widespread premalignant and malignant alterations, it is frequently not possible to entirely remove the tumour by surgery. This results in a high risk of tumour recurrence. Therefore, this PhD research aimed to develop photocatalytic nanoparticles (NPs) as completion of the traditional tumour therapy. These NPs are supposed to be incorporated by tumour cells and to induce photocatalytic cell death by UV light activation. TiO2 with convincing photocatalytic properties and an average size smaller than 20 nm should therefore be synthesized. NP biocompatibility, their uptake into cells and an efficient tumour targeting should be guaranteed by surface modification of the particles with dendritic organic molecules that allow a precise control of the surface charge of the particles as well as antibody coupling.A further objective was the combination of therapeutic and diagnostic properties within the NPsystem realized for example via introduction of a luminescent dye. This research was carried out at the University of Bordeaux (synthesis of organic molecules for particle functionalization) in cooperation with the Fraunhofer Institute for Silicate Research ISC in Würzburg, Germany (nanoparticle synthesis).

Les nanotubes de carbone (CNTs) sont une nouvelle forme allotropique du carbone, décrits pour la première fois à l’échelle atomique en 1991 par Iijima. Dans ce travail de thèse, les MWCNTs portant des charges cationiques ont été fonctionnalisés, avec pour objectif d’étudier leur aptitude à complexer des acides nucléiques pour obtenir un système de délivrance génétique. Initialement, nous avons fonctionnalisé les MWCNTs avec des dendrons portant à leur extrémité des groupes ammonium ou guanidinium et leur aptitude à complexer des acides nucléiques a été évaluée par électrophorèse en gel d’agarose. En outre, nous avons fonctionnalisé et caractérisé les MWCNTs avec un peptide ciblant les mitochondries et leur habilité à se localiser à l’intérieur de ces dernières a été étudié par différentes techniques microscopiques. Ensuite, nous avons doublementfonctionnalisé les CNTs avec un dendron de deuxième génération et avec le peptide de ciblage. La capacité de ce conjugué à complexer l’ADN a finalement été confirmée par électrophorèse en gel d’agarose. / Carbon nanotubes (CNTs) are a new allotropic form of carbon described at the atomic level in 1991 by Iijima. During my thesis, carbon nanotubes bearing cationic moieties have been functionalized, in order to study their ability to complex the genetic material to obtain a gene delivery system. Initially we have functionalized MWCNTs with dendrons bearing at their termini ammonium or guanidinium groups. Their ability to complex the genetic material has been evaluated through agarose gelelectrophoresis. Moreover, we have functionalized and characterized MWCNTs with a targeting peptide for mitochondria and their ability to localize inside this organelle was studied by different microscopic techniques. Then, we have double-functionalized MWCNTs with a dendron of second generation and with the targeting peptide and the ability of this conjugate to complex DNA was confirmed by agarose gel electrophoresis.

L’adamantane est un hydrocarbure polycyclique, rigide et assez encombrant. En médecine, plusieurs dérivés à base d’adamantane ont été développés notamment comme agent antiviraux. Facilement fonctionnalisés, sa conformation 3D permet d’amoindrir les encombrements stériques entre les différents groupements fonctionnels. Nous avons décidé d’utiliser ses propriétés pour concevoir des structures plus complexes, à savoir, des dendrons et des foldamers. Les dendrons sont des polymères synthétiques possédant des propriétés intéressantes. De par leurs tailles, ils sont considérés comme des nanoparticules et possèdent un ciblage passif des cellules cancéreuses. De plus, facilement fonctionnalisés ils peuvent être utilisés comme molécule cargo dans la vectorisation de principes actifs. Outre la vectorisation, les dendrons permettent d’améliorer les propriétés physico-chimiques d’un médicament (absorption, distribution, métabolisme, élimination et toxicité). Nous avons alors choisi de concevoir des dendrons à base d’adamantane. Ces derniers ont la particularité de ne pas posséder d’espaceur entre les molécules d'adamantane se qui les rend hautement rigides. L’analyse par microscopie électronique à transmission de différents dendrons a permis d’étudier leurs morphologies selon leurs fonctionnalisations ainsi que l’effet du solvant, de la concentration et du support sur leurs auto-assemblages. Dans un second temps, nous avons conçu un acide aminé basé sur l’adamantane. Cet acide g-aminé a ensuite été incorporé dans des séquences peptidiques et les effets de l’adamantane sur la structure secondaire des peptides ont été étudiés par dichroïsme circulaire. / Adamantane is a polycyclic hydrocarbon, rigid and quite bulky. In medicine, several adamantane-based derivatives have been developed especially as antiviral agents. Easily functionalized, its 3D well-defined structure considerably decrease the sterical hindrance between its different functional groups. In this context, we decided to use adamantane to build more complex structures such as dendrons and foldamers. Dendrons are synthetic polymers with interesting properties. Because of their size, they are considered as nanoparticles and possess a passive cancer cell targeting. In addition,they are easily functionalized and can be use as vector of drugs. Indeed, the dendrons improve the physochemical properties of a drug (absorption, distribution, metabolism, elimination and toxicity). We decided to combine adamantane and dendrons to build adamantane-based dendrons. However, these dendrons have the particularity of not having spacer between the adamantane moieties, thus, they are highly rigid. Transmission electron microscopy analysis of the different functionalized dendrons allowed to study their self-assembly capacity and their morphology according to their functional groups,the solvent, the concentration and the support. In a second step, we designed an amino acid based on adamantane. This g-amino acid has been introduced in a peptide backbone using solid phase peptide synthesis. Then, the effects of adamantane onto peptide secondary structures have been studied by circular dichroism.

No description available.

As doenças cardiovasculares são as principais causas de morte no Brasil e no mundo e constituem problema de saúde médico-social, de grande impacto econômico. As alterações no perfil lipídico e hematológico são fundamentais na formação da aterosclerose, considerando que o LDL (do inglês Low-Density Lipoprotein) e a agregação plaquetária estão envolvidos na formação dos trombos e, consequentemente, em eventos vaso-oclusivos. Entre os fármacos utilizados, encontram-se as estatinas. A rosuvastatina, um dos fármacos utilizados, é inibidora da hidroximetilglutaril coenzima A (HMG CoA) redutase e possui melhor perfil farmacodinâmico entre as estatinas, com maior potência e seletividade. O ácido acetilsalicílico, anti-inflamatório não-esteroide com atividade antiplaquetária mais difundido na terapia, é utilizado, por esse efeito, em associação com estatinas. Fatores limitantes para o uso da rosuvastatina e o ácido acetilsalicílico são: a baixa permeabilidade da rosuvastatina cálcica, e consequente baixa biodisponibilidade (biodisponibilidade absoluta 20%), e tempo de meia-vida do ácido acetilsalicílico de 6-7 h, o que leva à necessidade de elevadas doses e maior frequência de administração de ambos os fármacos. Visto que a associação das estatinas e do ácido acetilsalicílico promove melhor eficácia na prevenção e tratamento de doenças cardiovasculares, o objetivo foi aumentar a solubilidade da estatina e, consequentemente, a sua biodisponibilidade, e a meia-vida do ácido acetilsalicílico, juntamente com a diminuição da toxicidade desse último.. Por outro lado, considerando-se a importância dos dendrímeros como transportadores de fármacos na latenciação, propôs-se o planejamento e a síntese de pró-fármacos dendriméricos, potencialmente cardiovasculares, derivados da associação de rosuvastatina e ácido acetilsalicílico, utilizando etilenoglicol e pentaeritritol como núcleos e ácido L(-)-málico, ácido 2,2-bis(hidroximetil)propiônico e etilenoglicol, como espaçantes.. Obtiveram-se dois pró-fármacos, que se constituem em dendrons como parte dos dendrímeros planejados. O primeiro foi sintetizado pelo método convergente em duplo estágio e faz parte do bloco da camada externa do dendrímero I e o segundo, pela abordagem convergente clássica, sendo este o dendron do dendrímero II. Parte limitante na obtenção desses dendrímeros, além das etapas de purificação, são as etapas de desproteção. / Cardiovascular diseases have been the main causes of death in Brazil and in the world and are medical-social health problem with great economic impact. Alterations in the lipid hematological profiles are essentials in atherosclerosis, as LDL (Low-Density Lipoprotein) and the platelet aggregation are involved in the thrombus formation and, consequently, in occlusive vessel events. Among the drugs used to overcome those alterations are the statins. Rosuvastatin, one of the drugs used, is a hydroxymethylglutaryl coenzine A (HMG CoA) reductase inhibitor and it has the best pharmacodynamics profile among the statins, with higher potency and selectivity. Acetylsalicylic acid, a non-steroid anti-inflammatory agent with antiplatelet activity most disseminated in therapeutics, has been used in combination with statins due to this effect. Limited factors for the use of rosuvastatin and acetylsalycilic acid are the low permeability of the former, and consequently a low bioavailability (20% absolute bioavailability), and a 6 to 7 h half-life time of acetylsalycilic acid. Those factors lead to the need of high doses and higher frequency of administration of both drugs. Considering the combination of statins and acetylsalycilic acid promotes a better efficacy in either prevention or in the treatment of cardiovascular diseases, the objective of this work was to increase the rosuvastatin solubility and, consequently, its bioavailability, and the half-life time of acetylsalicylic acid, together with the decrease of its toxicity. On the other hand, considering the importance of dendrimers as drug carriers in prodrug approach, the design and synthesis of potentially cardiovascular dendrimer prodrugs derived from de combination of rosuvastatin and acetylsalicylic acid was proposed. With this goal, ethylene glycol and pentaerytritol were used as core and L(-)malic acid, 2,2-bis(hydroxymethyl)propionic acid and ethylene glycol were used as spacer groups. Two prodrug dendrons were obtained as part of the designed dendrimers. The first one was synthesized by two-step convergent method and it is part of the external layer block of dendrimer I. The second was obtained through classical convergent synthesis as the dendron of dendrimer II. The purification and deprotection steps showed to be the greatest obstacles for obtaining the proposed compounds.

As doenças cardiovasculares são as principais causas de morte no Brasil e no mundo e constituem problema de saúde médico-social, de grande impacto econômico. As alterações no perfil lipídico e hematológico são fundamentais na formação da aterosclerose, considerando que o LDL (do inglês Low-Density Lipoprotein) e a agregação plaquetária estão envolvidos na formação dos trombos e, consequentemente, em eventos vaso-oclusivos. Entre os fármacos utilizados, encontram-se as estatinas. A rosuvastatina, um dos fármacos utilizados, é inibidora da hidroximetilglutaril coenzima A (HMG CoA) redutase e possui melhor perfil farmacodinâmico entre as estatinas, com maior potência e seletividade. O ácido acetilsalicílico, anti-inflamatório não-esteroide com atividade antiplaquetária mais difundido na terapia, é utilizado, por esse efeito, em associação com estatinas. Fatores limitantes para o uso da rosuvastatina e o ácido acetilsalicílico são: a baixa permeabilidade da rosuvastatina cálcica, e consequente baixa biodisponibilidade (biodisponibilidade absoluta 20%), e tempo de meia-vida do ácido acetilsalicílico de 6-7 h, o que leva à necessidade de elevadas doses e maior frequência de administração de ambos os fármacos. Visto que a associação das estatinas e do ácido acetilsalicílico promove melhor eficácia na prevenção e tratamento de doenças cardiovasculares, o objetivo foi aumentar a solubilidade da estatina e, consequentemente, a sua biodisponibilidade, e a meia-vida do ácido acetilsalicílico, juntamente com a diminuição da toxicidade desse último.. Por outro lado, considerando-se a importância dos dendrímeros como transportadores de fármacos na latenciação, propôs-se o planejamento e a síntese de pró-fármacos dendriméricos, potencialmente cardiovasculares, derivados da associação de rosuvastatina e ácido acetilsalicílico, utilizando etilenoglicol e pentaeritritol como núcleos e ácido L(-)-málico, ácido 2,2-bis(hidroximetil)propiônico e etilenoglicol, como espaçantes.. Obtiveram-se dois pró-fármacos, que se constituem em dendrons como parte dos dendrímeros planejados. O primeiro foi sintetizado pelo método convergente em duplo estágio e faz parte do bloco da camada externa do dendrímero I e o segundo, pela abordagem convergente clássica, sendo este o dendron do dendrímero II. Parte limitante na obtenção desses dendrímeros, além das etapas de purificação, são as etapas de desproteção. / Cardiovascular diseases have been the main causes of death in Brazil and in the world and are medical-social health problem with great economic impact. Alterations in the lipid hematological profiles are essentials in atherosclerosis, as LDL (Low-Density Lipoprotein) and the platelet aggregation are involved in the thrombus formation and, consequently, in occlusive vessel events. Among the drugs used to overcome those alterations are the statins. Rosuvastatin, one of the drugs used, is a hydroxymethylglutaryl coenzine A (HMG CoA) reductase inhibitor and it has the best pharmacodynamics profile among the statins, with higher potency and selectivity. Acetylsalicylic acid, a non-steroid anti-inflammatory agent with antiplatelet activity most disseminated in therapeutics, has been used in combination with statins due to this effect. Limited factors for the use of rosuvastatin and acetylsalycilic acid are the low permeability of the former, and consequently a low bioavailability (20% absolute bioavailability), and a 6 to 7 h half-life time of acetylsalycilic acid. Those factors lead to the need of high doses and higher frequency of administration of both drugs. Considering the combination of statins and acetylsalycilic acid promotes a better efficacy in either prevention or in the treatment of cardiovascular diseases, the objective of this work was to increase the rosuvastatin solubility and, consequently, its bioavailability, and the half-life time of acetylsalicylic acid, together with the decrease of its toxicity. On the other hand, considering the importance of dendrimers as drug carriers in prodrug approach, the design and synthesis of potentially cardiovascular dendrimer prodrugs derived from de combination of rosuvastatin and acetylsalicylic acid was proposed. With this goal, ethylene glycol and pentaerytritol were used as core and L(-)malic acid, 2,2-bis(hydroxymethyl)propionic acid and ethylene glycol were used as spacer groups. Two prodrug dendrons were obtained as part of the designed dendrimers. The first one was synthesized by two-step convergent method and it is part of the external layer block of dendrimer I. The second was obtained through classical convergent synthesis as the dendron of dendrimer II. The purification and deprotection steps showed to be the greatest obstacles for obtaining the proposed compounds.

La biofonctionnalisation de surfaces de silice est une étape cruciale dans de nombreux domaines de biotechnologie tels que la biodétection ou la bioséparation. Le contrôle de l’état de surface entre les supports solides des matériaux et les espèces biologiques permet d’améliorer leurs performances de reconnaissance. Dans ce travail, nous avons développés des organosilanes fonctionnels dendritiques de première et de seconde génération pour la modification chimique de surface. Ces organosilanes dendritiques de type RSiX3 (X= Cl ou OMe3 ou OEt3) ont été greffés de manière covalente sur des surfaces de silice ou des surfaces de nanoparticules superparamagnétiques de type core-shell (gamma-Fe2O3/SiO2). La qualité des greffages a été analysée par AFM et TEM. Ils ont également été caractérisés par infrarouge, angle de contact et zêtamétrie. Ces surfaces modifiées par des molécules dendritiques ont montré une capacité à immobiliser des molécules biologiques comme la protéine A ou des anticorps de lapin. / Biofunctionalization of silica surfaces represents a crucial step for many applications in biotechnology such as biosensing and bioseparation. Monitoring the surface modification of the materials supports can improve their performances for the recognition of biological species. In this work, we have developed functional dendritic organosilanes of first and second generation for chemical modification of surfaces. These dendritic organosilanes RSiX3 (X = Cl or OMe3 or OEt3) were covalently grafted on planar silica or on core-shell superparamagnetic nanoparticles surfaces (gamma-Fe2O3/SiO2). The grafted surfaces were analyzed by AFM and TEM. They were also characterized by Infrared, contact angle and zetametry. These modified surfaces by dendritic molecules have shown high ability to immobilize biological molecules such as protein A or rabbit antibodies.

Chapter 1: Amphiphilic self-assembled systems as nanocarriers Nanocarriers are the nanometric size molecular assemblies that are used for the transport of small molecules into their non-solvating environments. These systems find major applications as drug delivery systems (DDS) in pharmacological research. These drug delivery systems improves solubility and stability of the drug molecules through encapsulation and also offer additional advantages like target specificity and stimuli responsive release of the drug molecules. Several types of DDS are reported in the literature, which can be prepared by a variety of processing techniques. Of these, molecular self- Chart 1: Developments in the design of amphiphilic nanocarriers assembly has attained considerable attention due to its greater tunability and control in the preparation of nanocarriers. In this chapter we discussed about the amphiphilic nanocarriers which are prepared through self-assembly of amphiphiles through hydrophobic interactions. Several developments in the area of amphiphilic nanocarriers such as di-block polymeric systems, dendritic systems and core-shell architectures are also mentioned. We also highlighted some recent developments in the design of amphiphilic nanocarriers through supramolecular interactions and advantages of such systems. Chapter 2: Bile acid derived dendrons and their application as nanocarriers Host-guest chemistry is well known for dendritic systems. To understand the influence of steric crowding, dendritic effect and importance of number of hydroxyl groups on the bile acid backbone in the host-guest chemistry of bile acid dendrons, we designed and synthesized a new series of C3 symmetric systems and studied the above-mentioned objectives through extraction of polar dyes into nonpolar media. Dye extraction experiments performed using trimeric molecules suggested that only the cholate derivatives (3 and 4) showed considerable extraction of the polar dyes into chloroform; deoxycholate derivatives did not show any extraction, thus emphasizing the importance of the number of hydroxyl groups for dye extraction in these molecular architectures. The effect of steric crowding at the core of these trimeric molecules was shown by efficient extraction of the dyes with the triethylbenzene core (4) compared to the benzene core (3). Greater influence of the aggregates in the case of triethylbenzene core on the extracted dye was also manifested in the Chart 2: Structures of the designed molecules 1-6 value of the induced circular dichroism signal. Surprisingly, a higher analogue in these molecular architectures showed lesser efficiency in dye extraction (on a per bile acid residue basis) compared to the trimers, suggesting a more compact structure for the higher analogue. This was supported by molecular modeling studies. Generality of these systems as nanocarriers for hydrophilic dyes was investigated by screening several other dyes and polar molecules, which are diverse in their structure and functionalities. All these experiments suggested a dependency of the extraction profile on the size of the dye molecule. This was also examined by dynamic light scattering studies, which showed larger size and wider distribution in the size of the aggregates in the case of larger dyes. We also demonstrated selective extraction of a single dye molecule from a blended food color (apple green) using one of the trimer (4) and demonstrated solvent dependent morphological changes in these compounds using electron microscopy. The self-assembly of these amphilic molecules at the air-water interface was studied through Langmuir monolayer studies. Chart 3: Structure of polar guest molecules (Cresol red (7). Erioglaucine (8), Eriochrome black T (9),) phenyl β-D-glucopyranoside (10) and Eosin B (11) Chapter 3: Design and synthesis of bile acid derived surfactants: Study of their aggregation and potential applications Bile acids are facially amphiphilic systems and their amphiphilicity can be improved by attaching polar groups on the bile acid back bone or by synthesizing oligomeric systems which show better self-assembly compared to their monomeric units. To study and improve the amphiphilicity of bile acids, we designed and synthesized a new tripodal surfactant system, with a phosphine oxide based central core to which the bile acids were attached through the C-3 position using click chemistry. Our molecular design also offers added advantage of studying the influence of the stereochemistry at the C-3 position on the aggregation of these molecular architectures. We synthesized trimeric systems with both cholic and deoxycholic acids attached to the central phosphine oxide core with α and β stereochemistry at the C-3 position. Aggregation of these molecules was studied by surface tension measurements, dye extraction studies and NMR. All these compounds showed aggregation at micromolar concentrations. NMR studies suggested changes in the structure of the aggregates at higher temperature and these changes were studied by DLS, which suggested thermodynamically stable monodispersed aggregates for cholic acid derivatives (13 and 15) at higher temperature. These aggregates are stable even after cooling to room temperature and with time. The aggregates of these derivatives were also characterized by atomic force microscopy. Gelation was observed in the case of α derivatives (12 and 13) in phosphate buffer (0.1 M) at pH 7.5 for both deoxy and cholic derivatives, which emphasized the influence of stereochemistry at C-3 position in these architectures. These gels were characterized by rheology experiments. Finally, the possible utility of these micellar systems as model systems to study photophysical processes was demonstrated through lanthanide sensitization experiments in these micellar solutions. Chart 4: Structure of the designed molecules Chapter 4: Synthesis of oligomeric bile acid-taurine conjugates: Study of their aggregation and efficiency in cholesterol solubilization Bile acids are bio-surfactants that are used for the emulsification of fats, vitamins etc. in our body. Bile salts also solubilize the excess cholesterol in our body through mixed micelle formation in the bile and when the bile gets saturated with cholesterol, it leads to cholesterol gallstone formation, which needs to be treated. Ursodeoxycholic acid (UDCA) is used as drug in some cases for the solubilization of (small) cholesterol gallstones, even though the efficiency to solubilize cholesterol is less for UDCA compared to the other bile acids (UDCA is less toxic than the others). So there is a need to develop new cholesterol solubilizing agents. Since oligomeric systems can aggregate better, we designed and synthesized two tetramer taurine conjugates, which differ in the spacer between the bile acid units. Since these conjugates are not soluble in water, their solubility and aggregation was studied in 10% MeOH/Water using pyrene fluorescence experiments. Aggregation studies suggested better aggregation for these molecules compared to their monomeric analogues. These aggregates were also characterized byDLS and electron microscopy. These systems were subsequently studied as nanocarriers for liphophilic dye molecules into aqueous media. Finally, the influence of oligomeric effect in cholesterol solubilization was investigated by cholesterol solubilization studied using these two tetramer taurine compounds and a control, sodium taurocholate. These studies suggested efficient solubilization of cholesterol by oligomers compared to monomeric analogues.(For structural formula pl see the abstract file)