Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first section of this thesis deals with the synthesis of substituted quinolines and its bioactivities against gap junction. Cancer cells are characterized by down regulated or altered gap junction intercellular communication (GJIC) activities; enhancement of GJIC would provide a pathway for the delivery of anticancer drugs. Our computational studies using Autodock found binding interactions between gap junction channels and substituted quionlines (code name PQs). Thus, a serial of PQ compounds were synthesized and their activities against GJIC were tested. Among these synthesized PQs, 6-Methoxy-8-[(3-aminopropyl) amino]-4- methyl-5-(3-trifluoromethyl- phenyloxy)quinoline (PQ1) can specifically enhance GJIC activity of T47D cells without affecting the normal MECs. The PQ1 induced apoptosis can spread throughout the gap juctions, consequently cause the decrease of cell viability and colony growth. PQ1 can attenuate tumor growth of xenograft tumors in Nu/Nu mice. Compound 7 (code PQ11) which has an IC50 of 15.6nM against T47D cancer cell, is a promising candidate for further pharmacological studies. The second section of this thesis deals with the synthesis and anticancer bioactivities of PEG-PEI based nanogels. Nanogels were synthesized, encapsulated with anticancer drugs, and loaded to stem cells. Stem cells can target at the cancer cell and release the nanogel and anticancer drug to kill the cancer cell. The nontoxic PEG-PEI nanogel which can be loaded to stem cells was successfully synthesized by doubly treatment of PEI with activated PEG. Based on this nontoxic nanogel, two other types of nanogels were synthesized. In one type of nanogel, an anticancer drug, SN38 was modified and attached to the nontoxic nanogel via a tetra-peptide linker. This tetra peptide can be recognized and cut by legumain, a protein that highly over expressed in many tumors, to release the drug to tumors. In the other type of nanogel, straptavidin was attached to the nanogel which can bind to biotin and recognized by tumor. The result indicated this type of nanogel can be loaded to stem cells within 15 minutes.

Nanogels are soft, deformable networks of cross-linked polymer swollen in water. Nanogels have the unique ability to swell in response to external physiological conditions. Their stimuli-responsive nature affects degradability, drug uptake and release, which can be exploited to create tunable drug delivery systems. The ability to alter the composition and structure of nanogels imparts advantageous characteristics for targeted drug delivery applications. Antipsychotic drugs (APDs) used to treat schizophrenia, a chronic neuropsychiatric disorder, are typically hydrophobic. Prolonged dosing causes neurological and metabolic side effects due to the systemic administration of drug. Patient adherence to APD administration is low, causing complications that contribute to the substantial burden of disease. APDs would benefit from nanogel encapsulation through improved solubility and controlled release kinetics to reduce the adverse side effects associated with typical administration protocols. This thesis presents the development of hydrophobized, biodegradable poly(oligoethylene glycol methacrylate) (POEGMA)-based nanogels to deliver APDs to the brain. Both an adaptation of conventional precipitation polymerization as well as a spontaneous self-assembly technique are utilized to synthesize nanogels containing different hydrophobic domains. Incorporation of cross-linkers with different modalities of biodegradability enable stimuli-responsive degradation and drug release. The effects on nanogel swelling, biodegradability, and APD uptake and release kinetics are explored in vitro. The preclinical application of these APD-loaded nanogels is evaluated using the minimally invasive intranasal (IN) route for delivery. We show that these nanogel delivery systems have therapeutic effects in terms of significantly altering a range of rodent behaviours, including locomotion inhibition, the onset of catalepsy, and improvement in pre-pulse inhibition, over extended periods of time in relation to current administration strategies. These drug-loaded nanogel delivery systems show potential to minimize the effective therapeutic dose by enhancing APD bioavailability via IN administration, thus reducing adverse outcomes and improving potential patient adherence to APD-based therapies in clinical use. / Thesis / Doctor of Philosophy (PhD) / Nanogels are soft, deformable polymer networks swollen in water with potential for drug delivery given their easy-to-tune physicochemical properties. However, the poor water solubility of many therapeutics, including antipsychotic drugs (APDs) used to treat schizophrenia, limits drug encapsulation within nanogels. In addition, conventional synthetic techniques produce materials that degrade into poorly-defined byproducts, causing toxicity concerns. This thesis presents novel strategies to incorporate hydrophobic domains and biodegradable bonds within poly(oligo ethylene glycol methacrylate) (POEGMA) nanogels. We demonstrate how these moieties affect nanogel swelling, degradability, cytocompatability as well as the uptake and release of clinically prescribed APDs. Intranasal (IN) administration of drug-loaded nanogels is studied as a non-invasive delivery alternative to improve drug bioavailability. The proposed nanogel-based drug delivery systems can decrease drug dose, minimize adverse side effects, and improve patient adherence to therapeutic regimens relying on APDs, demonstrating their potential for clinical application.

Les nanogels sont des macromolécules ramifiées solubles possédant une structure en réseau et de dimensions inférieures à 100 nm. La méthodologie récente de la copolymérisation radicalaire réticulante contrôlée permet d'accéder à de telles architectures polymères tout en contrôlant finement leur structure interne. Nous présentons dans ce travail: (i) l'étude préalable de systèmes modèles, permettant de dégager les conditions nécessaires à la synthèse de nanogels; (ii) l'application à la synthèse de nanogels hydrophiles valorisables de poly(alcool vinylique) et de poly(N-vinylpyrrolidone); (iii) une modélisation cinétique permettant de rendre compte des tendances observées expérimentalement et de prévoir les grandeurs caractéristiques de produits synthétisés par cette méthodologie. / Abstract

L'acide hyaluronique est un polysaccharide fortement hydraté. Grâce à sa présence naturelle dans le corps humain et aux nombreuses possibilités de modifications chimiques de ce polysaccharide, l'acide hyaluronique est un bon candidat pour la conception de transporteurs de principes actifs. Dans cette thèse, nous avons synthétisé différents types de dérivés du HA en milieu aqueux. Ceux-ci comprennent les dérivés alkylés du HA, HA-cyclodextrine conjugués et des copolymères «hybrides» composés de HA et d'un copolymère thermosensible de l'éthylène glycol.Basé sur la capacité d'accueillir des molécules hydrophobes paclitaxel dans leurs hydrophobes "nanocavités", nous avons ensuite montré la formation de multicouches de polyélectrolytes de capsules à partir de ces dérivés du HA. L'insertion des molécules paclitaxel dans la paroi des capsules a été réalisée par pré-complexation avec les dérivés du HA en solution, et ensuite déposition ces PTX-polyélectrolytes avec le poly(L-lysine) selon la technique de couche par couche.Dans les deux cas, les capsules chargées de PTX ont été trouvés qu'elles permettent de réduire la viabilité et la prolifération des cellules cancéreuses. Ces multicouches ouvrent de nouvelles voies vers des applications en nanomédecine, comme systèmes transporteurs de médicaments hydrophobes. L'acide hyaluronique modifié par maleimide a été réagit avec poly(diethyleneglycolmethacrylate - oligoethyleneglycolmethacrylate (poly(DEGMA-co-OEGMA)) modifié par thiol afin d'obtenir le copolymère «hybrides» thermosensible. La valeur de la LCST de ce copolymère de HA est autour de 35 °C en déterminant par les mesures du point de trouble des solutions. Au-dessus de cette température, le HA-poly(DEGMA-co-OEGMA) conduit à la formation des nanogels avec la capacité d'encapsuler des molécules hydrophobes dans leur domaine hydrophobe.Les nanogels chargés en PTX ont montré une cytotoxicité plus élevée avec des cellules du cancer surexprimant le récepteur CD44. Ces résultats suggèrent que ces nanogels thermosensible pourraient s'avérer être des candidats intéressants pour la libration thérapeutique dans le traitement de cancer. / Hyaluronic acid is a highly hydrated polysaccharide of great biological interest. It can be easily chemically modified, resulting in many kinds of functional polysaccharide derivatives. In this thesis, we have synthesized different types of HA derivatives in aqueous media. These comprise alkylated HA derivatives, HA-cyclodextrin conjugates, and hybrid copolymers made of HA and of a thermosensitive ethylene glycol copolymer. Based on the ability of alkylated HA and cyclodextrin grafted HA to accomodate hydrophobic molecules paclitaxel into their hydrophobic “nanocavities”, we then demonstrated the formation of polyelectrolyte multilayer capsules based on these HA derivatives. The loading of PTX in the nanoshell was achieved by first complexing PTX with HA derivatives in solution and then, depositing these PTX-containing polyelectrolytes alternately with poly(L-lysine) according to the layer-by-layer technique. In the two cases, the PTX loaded capsules were found to decrease the viability and proliferation of MDA MB 231 breast cancer cells, while unloaded capsules did not impact cell viability. Due to these promising results, these hydrophobic polysaccharide nanoshells open new avenues for applications of hydrophobic drug-carrier systems in nanomedicine.Thiol modified poly(diethyleneglycolmethacrylate - oligoethyleneglycolmethacrylate (poly(DEGMA-co-OEGMA)) was reacted with a HA-maleimide conjugate to obtain HA- poly(DEGMA-co-OEGMA). The LCST value of this HA-copolymer was determined to be around 35°C via turbidity measurements. At the body temperature, HA-copolymer was thus shown to self-assemble into nanogels with the ability to encapsulate hydrophobic molecules into their hydrophobic domain. . In vitro cell culture studies showed that with incorporating the hydrophobic anti-cancer drug paclitaxel, the nanogels exhibited high efficiency and selectivity in the eradication of CD44 positive human ovarian cancer cells. These results suggest that these temperature-triggered nanogels hold great potential for the delivery of chemotherapeutics in anti-cancer therapy.

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22469号 / 工博第4730号 / 新制||工||1739(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 秋吉 一成, 教授 近藤 輝幸, 教授 梅田 眞郷 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Ce travail décrit d'abord l’élaboration de nanogels hydrophiles stimulables, sensibles à un changement de pH et à un environnement où les propriétés d’oxydo-réduction peuvent varier. Ils ont été synthétisés en milieu dilué, d’une part, et en émulsion inverse, d’autre part; dans les deux cas à partir d’un copolymère statistique composé d’unités 2-éthyl-2-oxazoline et éthylène imine. Ces nanogels n’ont pas montré d’interactions spécifiques avec des protéines telles que la BSA et se sont avérés non-toxiques in vitro. Une plateforme à base d’un copolymère POx statistique porteur de fonctions aldéhydes a par ailleurs permis d’accéder à une librairie de POx, incluant des structures greffées et réticulées. Enfin, l’autoassemblage en solution d’un copolymère à blocs de type poly(2-methyl-oxazoline)-bpoly(2-isopropyl-2-oxazoline) (PMeOx-b-PiPrOx), a été étudié en détail. Des micelles ont été observées à des temps courts au-dessus du point trouble du PiPrOx. Pour des temps plus longs, la formation de fibres et de micelles réticulées physiquement ont été mise en évidence, comportement expliqué par la cristallisation des chainesde PiPrOx stabilisées par les blocs PMeOx hydrophiles. / This PhD work is based on the design of poly(2-oxazoline) (POx)hydrogels and nanogels, by chemical or physical cross-linking, aimed to be used for biomedical applications. Nanogels were first prepared in dilute media and in inverse emulsion based on a statistical copolymer made of 2-ethyl-2-oxazoline and ethyleneimine units. These stimuli-responsive nanogels were swelling in acidic media and were cleaved in reductive environment. They proved to be non-cytotoxic and act as protein repellent. Second, a reactive platform based on a statistical POx polymerbearing aldehyde functionalities was engineered, enabling the synthesis of graft and cross-linked POx. Last, a block copolymer made of 2-methyl- and 2-isopropyl-2-oxazoline units, proved to self-assemble into micelles when heated above its LCST,for a short period of time (< 1h30). When annealed for a longer time (> 1h30),crystallization-driven self-assembly led to the formation of different morphologies(fiber rods and cross-linked micelles).

L’utilisation de nanovecteurs pour la livraison contrôlée de principes actifs est un concept commun de nous jours. Les systèmes de livraison actuels présentent encore cependant des limites au niveau du taux de relargage des principes actifs ainsi que de la stabilité des transporteurs. Les systèmes composés à la fois de nanovecteurs (liposomes, microgels et nanogels) et d’hydrogels peuvent cependant permettre de résoudre ces problèmes. Dans cette étude, nous avons développé un système de livraison contrôlé se basant sur l’incorporation d’un nanovecteur dans une matrice hydrogel dans le but de combler les lacunes des systèmes se basant sur un vecteur uniquement. Une telle combinaison pourrait permettre un contrôle accru du relargage par stabilisation réciproque. Plus spécifiquement, nous avons développé un hydrogel structuré intégrant des liposomes, microgels et nanogels séparément chargés en principes actifs modèles potentiellement relargués de manière contrôlé. Ce contrôle a été obtenu par la modification de différents paramètres tels que la température ainsi que la composition et la concentration en nanovecteurs. Nous avons comparé la capacité de chargement et la cinétique de relargage de la sulforhodamine B et de la rhodamine 6G en utilisant des liposomes de DOPC et DPPC à différents ratios, des nanogels de chitosan/acide hyaluronique et des microgels de N-isopropylacrylamide (NIPAM) à différents ratios d’acide méthacrylique, incorporés dans un hydrogel modèle d’acrylamide. Les liposomes présentaient des capacités de chargement modérés avec un relargage prolongé sur plus de dix jours alors que les nanogels présentaient des capacités de chargement plus élevées mais une cinétique de relargage plus rapide avec un épuisement de la cargaison en deux jours. Comparativement, les microgels relarguaient complétement leur contenu en un jour. Malgré une cinétique de relargage plus rapide, les microgels ont démontré la possibilité de contrôler finement le chargement en principe actif. Ce contrôle peut être atteint par la modification des propriétés structurelles ou en changeant le milieu d’incubation, comme l’a montré la corrélation avec les isothermes de Langmuir. Chaque système développé a démontré un potentiel contrôle du taux de relargage, ce qui en fait des candidats pour des investigations futures. / Controlled delivery of active compounds using nanoscale carriers is nowadays a common concept, but there are still limitations in current delivery systems related to active compound release rate and nanocarriers stability. To address these limitations, delivery systems can be made to incorporate both nanocarriers (liposomes, microgels and nanogels) and hydrogels. In this study, we have developed controlled delivery systems by combining different carriers in order to overcome deficiencies observed in systems using only one type of carrier. Such a combination could lead to an enhanced controlled release delivery system through synergistic stabilization. More specifically, we created a structured hydrogel embedded with either liposomes, microgels, or nanogels, each loaded with model active compounds that would be released in a controlled fashion by manipulating the temperature of release medium and nanocarriers composition and concentration. We compared drug loading and release kinetics of sulforhodamine B from liposomes (composed of DOPC and DPPC at different ratios) and nanogels (chitosan/hyaluronic acid) embedded in acrylamide hydrogels. We also compared drug loading and release kinetics of rhodamine 6G from microgels of N-isopropylacrylamide (NIPAM) with different ratios of methacrylic acid embedded in acrylamide hydrogel. Liposomes demonstrated a moderate drug loading capacity with sustained release for over ten days, while nanogels showed high drug loading but faster release kinetics, exhausting their contents within two days. Comparatively, microgels completely released their content within a day. Despite their faster release kinetics, microgels have shown the capacity to be finely tuned for efficient drug loading. The Langmuir isotherms indicated that it can be achieved by altering their structural properties or by changing their incubation medium. Each developed system has demonstrated a potential in controlling the release rate, which makes them candidates for further investigations in the future.

A parte inicial deste estudo consistiu da síntese de HMSPP (Polipropileno com Alta Resistência do Fundido) também chamado polipropileno modificado por irradiação gama, a partir de iPP (polipropileno isotático) em presença de acetileno sob pressão de 110 kPa e irradiado com &gamma; (gama) de fonte de 60Co nas doses de 5; 12,5 e 20 kGy. A fração gel das amostras foi determinada pela extração de componentes solúveis em xileno. A parte solúvel das amostras foi decantada com deposição do gel em lâminas de vidro, até total volatilização do xileno à temperatura ambiente de 25 °C. À parte solúvel da amostra com 12,5 kGy adicionaram-se nanopartículas de prata (NPsAg) nas proporções de: 0,25; 0,5; 1,0; 2,0 e 4,0% em massa. Estas amostras foram caracterizadas por: microscopia eletrônica de varredura e espectroscopia de energia dispersiva (MEV/EDS), espectroscopia no infravermelho (FTIR), microscopia eletrônica de varredura com emissão de campo (MEV-EC), microscopia de força atômica (MFA), calorimetria exploratória diferencial (DSC), difração de raios X (DRX), redução da unidade formadora de colônias (UFC) (%) e teste de citotoxicidade. Neste estudo da morfologia, observou-se a formação de microgéis de polipropileno na ordem crescente PP 5 kGy < PP 12,5 kGy < 20 kGy. Constatou-se a existência de estruturas nanométricas de géis de polipropileno (nanogéis e nanofibras) nas amostras de PP 12,5 kGy e PP 20 kGy. Os nanogéis são formações reticuladas, ramificadas, e emaranhadas, nucleadas em regiões de incidência de alta concentração de energia (spurs) em uma amostra irradiada. Nos testes de avaliação da atividade bactericida dos géis com NPsAg observou-se eficiência biocida para E. coli e S. aureus a partir de 1% de NPsAg e no teste de citotoxicidade as amostras foram caracterizadas como não citotóxicas para células de mamíferos. Em uma segunda etapa deste trabalho foram produzidos filmes da blenda de iPP e PP modificado (50/50) em uma extrusora de dupla rosca. Adicionou-se ao processamento NPsAg nas proporções de: 0,1; 0,25; 0,5; 1,0; 1,0 PVP; 2,0 e 4,0% em massa. Os filmes foram caracterizados por: calorimetria exploratória diferencial (DSC), análise de termogravimetria (TGA), difração de raios X (DRX), microscopia eletrônica de varredura (MEV), espectroscopia de energia dispersiva (EDS), espectroscopia de ultravioleta-visível (UV-Vis), microscopia eletrônica de transmissão (MET), redução da unidade formadora de colônias (UFC) (%), teste de sensibilidade a antimicrobianos por disco de difusão e teste de citotoxicidade. Os filmes analisados apresentaram pontos de aglomeração de prata e regiões com distribuição homogênea das partículas. O efeito bactericida com a interação entre a prata, e E. coli, P. aeruginosa e S. aureus foi constatado para o filme de PP 1%NPsAg PVP Poli(N-vinil-2-pirrolidona). No teste de difusão o resultado obtido para PP 1% NPsAg PVP foi 100% positivo com essas bactérias. Os filmes não são considerados citotóxicos para células de mamíferos. / The study consists of the synthesis of HMSPP (polypropylene with high melt strength), also called polypropylene modified by gamma irradiation from iPP (isotactic polypropylene) in presence of acetylene at 110 kPa pressure and irradiated with &gamma; of 60Co source at doses of 5, 12.5 and 20 kGy. The gel fraction of the samples was determined by extracting in xylene. The soluble portion of the samples was decanted to deposition on glass substrate until complete volatilization of xylene at room temperature of 25 °C. On the soluble portion of 12.5 kGy irradiated sample were added silver nanoparticles (AgNPs) in proportions of 0.25, 0.5, 1.0, 2.0 and 4.0 wt%. These gel samples were characterized by: scanning electron microscopy/energy dispersive spectroscopy (SEM / EDS), infrared spectroscopy (FTIR), scanning electron microscopy with field emission (FE-SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), reduction of colony forming unit (CFU) (%) and cytotoxicity assay. In this study of the morphology, it has been observed the formation of microgels in polypropylene increasing with the dose PP 5 kGy < PP 12.5 kGy < 20 kGy. Nanoscale structures of gels polypropylene (nanogels and nanofibers) were found in samples of PP 12.5 kGy and 20 kGy. The nanogels are formation of crosslinking, branching and entanglement that are nucleated in regions of high energy concentration (spurs) of one irradiated sample. Efficiency in tests of bactericide activity of the gels with AgNPs was observed versus E. coli and S. aureus from 1% AgNPs and non cytotoxicity were characterized in those samples for mammalian cells. In a second stage of this work films of the blend of PP and modified PP (50/50) were produced in a twin screw extruder. AgNPs were added to the extrusion processing in proportions of 0.1; 0.25; 0.5; 1.0; 1.0 PVP; 2.0 and 4.0 wt%. The films obtained were characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), reduction of colony forming unit (CFU) (%), antimicrobial susceptibility testing by disk diffusion and cytotoxicity assay. The films analyzed showed agglomeration of silver points and regions with homogeneous distribution of the particles. The bactericide effect with the interaction between silver and E. coli, P. aeruginosa and S. aureus was found for PP film 1% NPsAg Polyvinylpyrrolidone (PVP). In the diffusion test for PP 1% AgNPs (PVP) was obtained 100%positive result for those bacteria. The films were not cytotoxic to mammalian cells.

A parte inicial deste estudo consistiu da síntese de HMSPP (Polipropileno com Alta Resistência do Fundido) também chamado polipropileno modificado por irradiação gama, a partir de iPP (polipropileno isotático) em presença de acetileno sob pressão de 110 kPa e irradiado com &gamma; (gama) de fonte de 60Co nas doses de 5; 12,5 e 20 kGy. A fração gel das amostras foi determinada pela extração de componentes solúveis em xileno. A parte solúvel das amostras foi decantada com deposição do gel em lâminas de vidro, até total volatilização do xileno à temperatura ambiente de 25 °C. À parte solúvel da amostra com 12,5 kGy adicionaram-se nanopartículas de prata (NPsAg) nas proporções de: 0,25; 0,5; 1,0; 2,0 e 4,0% em massa. Estas amostras foram caracterizadas por: microscopia eletrônica de varredura e espectroscopia de energia dispersiva (MEV/EDS), espectroscopia no infravermelho (FTIR), microscopia eletrônica de varredura com emissão de campo (MEV-EC), microscopia de força atômica (MFA), calorimetria exploratória diferencial (DSC), difração de raios X (DRX), redução da unidade formadora de colônias (UFC) (%) e teste de citotoxicidade. Neste estudo da morfologia, observou-se a formação de microgéis de polipropileno na ordem crescente PP 5 kGy < PP 12,5 kGy < 20 kGy. Constatou-se a existência de estruturas nanométricas de géis de polipropileno (nanogéis e nanofibras) nas amostras de PP 12,5 kGy e PP 20 kGy. Os nanogéis são formações reticuladas, ramificadas, e emaranhadas, nucleadas em regiões de incidência de alta concentração de energia (spurs) em uma amostra irradiada. Nos testes de avaliação da atividade bactericida dos géis com NPsAg observou-se eficiência biocida para E. coli e S. aureus a partir de 1% de NPsAg e no teste de citotoxicidade as amostras foram caracterizadas como não citotóxicas para células de mamíferos. Em uma segunda etapa deste trabalho foram produzidos filmes da blenda de iPP e PP modificado (50/50) em uma extrusora de dupla rosca. Adicionou-se ao processamento NPsAg nas proporções de: 0,1; 0,25; 0,5; 1,0; 1,0 PVP; 2,0 e 4,0% em massa. Os filmes foram caracterizados por: calorimetria exploratória diferencial (DSC), análise de termogravimetria (TGA), difração de raios X (DRX), microscopia eletrônica de varredura (MEV), espectroscopia de energia dispersiva (EDS), espectroscopia de ultravioleta-visível (UV-Vis), microscopia eletrônica de transmissão (MET), redução da unidade formadora de colônias (UFC) (%), teste de sensibilidade a antimicrobianos por disco de difusão e teste de citotoxicidade. Os filmes analisados apresentaram pontos de aglomeração de prata e regiões com distribuição homogênea das partículas. O efeito bactericida com a interação entre a prata, e E. coli, P. aeruginosa e S. aureus foi constatado para o filme de PP 1%NPsAg PVP Poli(N-vinil-2-pirrolidona). No teste de difusão o resultado obtido para PP 1% NPsAg PVP foi 100% positivo com essas bactérias. Os filmes não são considerados citotóxicos para células de mamíferos. / The study consists of the synthesis of HMSPP (polypropylene with high melt strength), also called polypropylene modified by gamma irradiation from iPP (isotactic polypropylene) in presence of acetylene at 110 kPa pressure and irradiated with &gamma; of 60Co source at doses of 5, 12.5 and 20 kGy. The gel fraction of the samples was determined by extracting in xylene. The soluble portion of the samples was decanted to deposition on glass substrate until complete volatilization of xylene at room temperature of 25 °C. On the soluble portion of 12.5 kGy irradiated sample were added silver nanoparticles (AgNPs) in proportions of 0.25, 0.5, 1.0, 2.0 and 4.0 wt%. These gel samples were characterized by: scanning electron microscopy/energy dispersive spectroscopy (SEM / EDS), infrared spectroscopy (FTIR), scanning electron microscopy with field emission (FE-SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), reduction of colony forming unit (CFU) (%) and cytotoxicity assay. In this study of the morphology, it has been observed the formation of microgels in polypropylene increasing with the dose PP 5 kGy < PP 12.5 kGy < 20 kGy. Nanoscale structures of gels polypropylene (nanogels and nanofibers) were found in samples of PP 12.5 kGy and 20 kGy. The nanogels are formation of crosslinking, branching and entanglement that are nucleated in regions of high energy concentration (spurs) of one irradiated sample. Efficiency in tests of bactericide activity of the gels with AgNPs was observed versus E. coli and S. aureus from 1% AgNPs and non cytotoxicity were characterized in those samples for mammalian cells. In a second stage of this work films of the blend of PP and modified PP (50/50) were produced in a twin screw extruder. AgNPs were added to the extrusion processing in proportions of 0.1; 0.25; 0.5; 1.0; 1.0 PVP; 2.0 and 4.0 wt%. The films obtained were characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), reduction of colony forming unit (CFU) (%), antimicrobial susceptibility testing by disk diffusion and cytotoxicity assay. The films analyzed showed agglomeration of silver points and regions with homogeneous distribution of the particles. The bactericide effect with the interaction between silver and E. coli, P. aeruginosa and S. aureus was found for PP film 1% NPsAg Polyvinylpyrrolidone (PVP). In the diffusion test for PP 1% AgNPs (PVP) was obtained 100%positive result for those bacteria. The films were not cytotoxic to mammalian cells.

L'acide hyaluronique est un polysaccharide fortement hydraté. Grâce à sa présence naturelle dans le corps humain et aux nombreuses possibilités de modifications chimiques de ce polysaccharide, l'acide hyaluronique est un bon candidat pour la conception de transporteurs de principes actifs. Dans cette thèse, nous avons synthétisé différents types de dérivés du HA en milieu aqueux. Ceux-ci comprennent les dérivés alkylés du HA, HA-cyclodextrine conjugués et des copolymères "hybrides" composés de HA et d'un copolymère thermosensible de l'éthylène glycol.Basé sur la capacité d'accueillir des molécules hydrophobes paclitaxel dans leurs hydrophobes "nanocavités", nous avons ensuite montré la formation de multicouches de polyélectrolytes de capsules à partir de ces dérivés du HA. L'insertion des molécules paclitaxel dans la paroi des capsules a été réalisée par pré-complexation avec les dérivés du HA en solution, et ensuite déposition ces PTX-polyélectrolytes avec le poly(L-lysine) selon la technique de couche par couche.Dans les deux cas, les capsules chargées de PTX ont été trouvés qu'elles permettent de réduire la viabilité et la prolifération des cellules cancéreuses. Ces multicouches ouvrent de nouvelles voies vers des applications en nanomédecine, comme systèmes transporteurs de médicaments hydrophobes. L'acide hyaluronique modifié par maleimide a été réagit avec poly(diethyleneglycolmethacrylate - oligoethyleneglycolmethacrylate (poly(DEGMA-co-OEGMA)) modifié par thiol afin d'obtenir le copolymère "hybrides" thermosensible. La valeur de la LCST de ce copolymère de HA est autour de 35 °C en déterminant par les mesures du point de trouble des solutions. Au-dessus de cette température, le HA-poly(DEGMA-co-OEGMA) conduit à la formation des nanogels avec la capacité d'encapsuler des molécules hydrophobes dans leur domaine hydrophobe.Les nanogels chargés en PTX ont montré une cytotoxicité plus élevée avec des cellules du cancer surexprimant le récepteur CD44. Ces résultats suggèrent que ces nanogels thermosensible pourraient s'avérer être des candidats intéressants pour la libration thérapeutique dans le traitement de cancer.