Les aérogels sont des matériaux nano-structurés ultralégers, hautement poreux et présentant une surface spécifique élevée. Les bio-aérogels sont une nouvelle génération d'aérogels entièrement bio-sourcés, offrant de ce fait de grands potentiels pour des applications à l’interface avec le vivant tout en valorisant la biomasse. Dans le cadre de cette thèse, la pectine a été utilisée pour produire des bio-aérogels. Deux principaux objectifs ont été atteints : • Le premier était de déterminer et de maîtriser les corrélations existantes entre les caractéristiques de la pectine et les conditions de préparation d’une part, avec la structure interne de l'aérogel et ses propriétés physico-chimiques d’autre part. • Le second était d’évaluer et développer les aérogels de pectine pour deux applications distinctes : l'isolation thermique et la libération de médicaments. Il a été établi que les différents mécanismes de formation du réseau, la gélification et la séparation de phase, jouaient un rôle majeur sur la morphologie et les propriétés finales de l'aérogel. La conductivité thermique des aérogels de pectine s'est révélée très faible, de l'ordre de 0,015 à 0,020 W/(m.K), et a présenté une courbe de dépendance en forme de U avec leurs densités. Les aérogels ont également été utilisés en tant que matrices supports de médicament. Les cinétiques de libération du médicament en milieu liquide ont été corrélées aux structures et densités des aérogels de pectine. Des aérogels composites, de type cellulose-pectine et silice-pectine, ont été préparés et utilisés comme supports de médicament menant à une libération prolongée du principe actif dans le temps. Dans cette thèse, nous avons mis en évidence le potentiel élevé des aérogels de pectine utilisés en tant que biomatériaux avancés, versatiles et aux fonctionnalités ajustables. / Aerogels are ultra-light, highly porous and nano-structured materials with high specific surface area. Bio-aerogels are a new generation of aerogels that are fully biomass-based, which opens up a lot of potentials in biomass valorization and life science applications. In this work pectin was used to produce bio- aerogels. Two main objectives were achieved : • The first was to understand and correlate the characteristics of pectin and the preparation conditions with the internal structure of aerogel and its physico-chemical properties. • The second was to evaluate and develop pectin aerogels as advanced bio-materials for the two different applications : thermal insulation and drug delivery. Various mechanisms of network formation, gelation and non-solvent induced phase separation, were demonstrated to play a very important role in aerogel morphology and properties. Thermal conductivity of pectin aerogels was very low, around 0.015 - 0.020 W/(m.K), and showing U-shape dependence on density. When used as drug delivery matrices, the kinetics of drug release was correlated with pectin aerogels’ structure and density. Composite cellulose-pectin and silica-pectin aerogels were synthesized and also used as drug carriers; a prolonged release was recorded. A high potential of pectin aerogels to be used as versatile bio-materials with advanced tunable functionalities was demonstrated.

La frequence elevee et les consequences considerables des maladies parodontales sur la qualite de vie orale et la sante generale font de ces pathologies une preoccupation de sante publique. Le developpement de traitements innovants est un moteur essentiel du progres dans la prise en charge de ces maladies. Ce travail s’interesse a l’utilisation d’agents antimicrobiens (non-antibiotiques) et anti-inflammatoires comme adjuvants au debridement mecanique des poches parodontales. Il est consacre a la mise au point et a l’optimisation d’une forme galenique appelee implant forme in-situ (IFIS), a base de polymeres biocompatibles et resorbables, concue pour le traitement des poches parodontales. Ce dispositif est injecte dans la lesion ou il libere de facon prolongee une combinaison d’antiseptique (chlorhexidine) et d’anti-inflammatoire (ibuprofene). Nos resultats montrent (i) in-vitro la superiorite de l’IFIS en termes de proprietes mecaniques et antimicrobiennes sur des systemes actuellement commercialises pour le meme usage et (ii) in-vivo, chez l’animal, un effet positif de l’IFIS sur la cicatrisation parodontale. Cette etude valide l’usage d’IFIS a base d’acide Poly(D,L-lactique-co-glycolique) (PLGA) comme support de liberation controlee de principes actifs dans la poche parodontale. Elle montre egalement que la combinaison d’un antiseptique et d’un anti-inflammatoire au sein du meme systeme de liberation locale pourrait ameliorer le traitement des parodontites tout en limitant le recours aux antibiotiques. / Periodontal diseases are highly prevalent oral conditions which strongly impact the oral quality of life and general health. Progress in the management of periodontal diseases depends, at least partly, on the development of novative and effective periodontal treatments. This work is concerned with the use of non-antibiotic antimicrobials and antiinflammatory drugs as adjunctive periodontal therapy. The aim was to develop a novel polymer-based, biocompatible and resorbable local drug delivery system (in-situ forming implants -ISFI-), which could be injected into periodontal pockets and control the delivery of both an antiseptic (chlorhexidine) and an anti-inflammatory agent (Ibuprofen). The physical key properties and antimicrobial activity of the proposed implants were very promising in vitro suggesting an improvement as compared to currently marketed drug delivery systems for periodontitis treatment. In vivo results are consistent with the latters, showing a positive effect of ISFI on periodontal wound healing in an experimental mice model of periodontitis. Data from this study support Poly(D,L-lactic-co-glycolic) acid (PLGA) as an attractive formulation for local drug-delivery into periodontal pockets. Our results further suggest that the local delivery of both an antiseptic and an anti-inflammatory drug is a promising adjunctive treatment of periodontitis. This should additionnaly reduce the use of systemic antibiotics in periodontal treatment and contribute to the combat against the development of bacterial resistances.

Transdermal drug delivery systems (TDDSs) play important roles in therapy due to distinct advantages over other forms and types of drug application. While common TDDS patches mainly consist of polymeric matrices so far, inorganic carriers show numerous advantages such as high mechanical stability, possible re-use and re-loading of drugs, and a broad chemical compatibility with therapeutically relevant compounds and chemical enhancers. Mesoporous glasses can be prepared in different monolithic shapes, and offer a particularly wide range of possible pore volumes, pore diameters, and specific surface areas. Further, they show high loading capacities and favorable physical, technical, and biological properties. Here, we explored for the first time monolithic SiO2- based carriers as sustained release systems of therapeutic drugs. In an ideally stirred vessel as model system, we systematically analyzed the influence of pore diameter, pore volume, and the dimensions of glass monoliths on the loading and sustained release of different drugs, including anastrozole, xylazine, imiquimod, levetiracetam, and flunixin. Through multilinear regression, we calculated the influence of different parameters on drug loading and diffusion coefficients. The systematic variation of the mesoporous glass properties revealed pore volumes and drug loading concentrations, but not pore diameter or pore surface area as important parameters of drug loading and release kinetics. Other relevant effectors include the occurrence of lateral diffusion within the carrier and drug-specific properties such as adsorption. The structure–property relationships derived from our data will allow further fine-tuning of the systems according to their desired properties as TDDS, thus guiding towards optimal systems for their use in transdermal drug applications

Les hydrogels sont des matériaux aux propriétés modulables dont la dégradation peut être contrôlée. Du fait de leur biocompatibilité, ils peuvent être utilisés afin de protéger les médicaments labiles et ainsi favoriser l’administration de traitements médicaux, d’où l’intérêt croissant de développer ces matériaux. Depuis quelques années, ils font l’objet de nombreuses recherches, que ce soit en ingénierie tissulaire, détection de mouvement, régénération de tissus ou pour le relargage de médicaments. Ce projet de thèse porte sur la formation d’hydrogels à base d’α-cyclodextrine et de polyéthylène glycol 20K ainsi que sur l’étude de leur capacité de relargage de principes actifs. Ces composés ont la capacité de former des complexes d’inclusion, créant ainsi un collier de perle, appelés pseudopolyrotaxane. Ensuite, ils seront modifiés pour créer des hydrogels de polyrotaxanes grâce à l’ajout de groupement bloquants. Finalement, nous formerons des hydrogels à point de réticulations glissant après avoir relié deux polyrotaxanes par leur macrocycle. À l’aide d’études rhéologiques, nous avons montré une amélioration des propriétés mécaniques des hydrogels proportionnelle à l’apport de liaisons chimique. Les groupements bloquants permettent d’éviter la désinclusion tandis que les réticulations apportent un effet poulie, les rendant exceptionnellement élastique. Ces hypothèses sont validées par les études structurales. Et nos hydrogels se sont révélés non toxiques pour les cellules humaines et ces résultats confirment leur biocompatibilité. Les hydrogels de pseudopolyrotaxanes sont les plus écologiques et les plus appropriés pour une application locale cutanée. Les hydrogels de polyrotaxanes, plus stables, peuvent être utilisés pour des applications locales prolongées ou par injection. Cependant, nos hydrogels de polyrotaxanes réticulés devront être modifiés afin de permettre un relargage contrôlé, car leur extrême stabilité pourrait entraver leur dégradation lors d'une injection sous-cutanée malgré leurs propriétés mécaniques exceptionnelles. / Hydrogels are materials with tunable properties whose degradation can be controlled. Because of their biocompatibility, they can be used to protect labile drugs and thus facilitate the administration of medical treatments, hence the growing interest in developing these materials. In recent years, they have been the subject of numerous studies, whether in tissue engineering, motion sensing, tissue regeneration or drug delivery. This project focuses on the formation of hydrogels based on α-cyclodextrin and polyethylene glycol 20K and the study of their drug release capacity. These compounds can form inclusion complexes, forming a pearl necklace called pseudopolyrotaxane. They will then be modified to form polyrotaxane hydrogels by adding blocking groups. Finally, we will form hydrogels with sliding cross-linking points after linking two polyrotaxanes through their macrocycle. Through rheological studies, we have demonstrated an improvement in the mechanical properties of the hydrogels proportional to the introduction of chemical bonds. Blocking groups prevent desorption, while cross-linking provides a pulley effect, making them exceptionally elastic. These hypotheses are supported by structural studies. Our hydrogels have been shown to be non-toxic to human cells, confirming their biocompatibility. Pseudopolyrotaxane hydrogels are the most environmentally friendly and suitable for local cutaneous application. Polyrotaxane hydrogels are more stable and can be used for prolonged local applications or by injection. However, our cross-linked polyrotaxane hydrogels will need to be modified to allow controlled release, as their extreme stability could hinder their degradation during subcutaneous injection, despite their exceptional mechanical properties.

<p dir="ltr">Opioid use disorder (OUD) presents a challenging and nuanced condition with potential for debilitating social and physical consequences. Patients with OUD have access to treatment options, but they may encounter issues such as diversion, invasiveness, or poor adherence. With over 2.5 million adults in the US experiencing OUD as of 2021, the need for an OUD treatment that overcomes these challenges is clear. One available treatment method is Sublocade®, a PLGA-based in situ forming implant (ISFI) that releases buprenorphine. This treatment shows promise due to its physician administered extended release design, which addresses many current issues in OUD treatment. However, the practicality of this treatment remains a challenge due to its monthly injection requirement. To address this, we investigated how altering ISFI components impacts the timeframe of buprenorphine release from a PLGA-based ISFI. Our focus was on evaluating factors that lead to extended buprenorphine release while maintaining zero-order release. We varied polymer-to-solvent ratios, drug percentage, and solvent composition, assessing their effects through drug release studies. We also conducted SEM imaging and swelling/erosion studies to evaluate polymer behavior and implant microstructure, gaining further insights into drug release mechanisms. Our drug release studies revealed that higher buprenorphine content in the implant significantly reduced total drug release and linearized drug release patterns. Decreasing the polymer-to-solvent ratio similarly linearized drug release and reduced drug burst, although the overall amount of drug released over time remained similar. Introducing Triacetin (TA) as a solvent helped reduce drug burst and maintain release linearity in lower drug content implants. In higher drug content implants, TA appeared to increase drug release over time, likely due to degradation processes indicated by high swelling and increased degradation observed in SEM imaging. Erosion studies showed less implant erosion with higher drug loading, aligning with release study observations. In conclusion, solvent type and drug content significantly influence buprenorphine release in ISFI systems and should be carefully considered when designing extended release systems similar to Sublocade®.</p>

Tesis por compendio / [ES] La presente tesis doctoral, titulada "Diseño y desarrollo de nuevos nanodispositivos con puertas biomoleculares para la liberación dirigida y controlada de fármacos", está centrada en el diseño, síntesis, caracterización y evaluación in vitro de nuevos nanosistemas híbridos orgánicos-inorgánicos como estrategias innovadoras para la administración dirigida y controlada de moléculas terapéuticas. El primer capítulo de este trabajo es una introducción general que define el contexto en el que se sitúan los proyectos llevados a cabo a lo largo de esta tesis. En particular, se describe el concepto de nanomedicina, así como las principales estrategias para el desarrollo de dispositivos nanofarmacéuticos eficientes y los desafíos que esto conlleva. Además, se presentan brevemente los materiales mesoporosos de sílice. Sucesivamente, se presentan los objetivos generales que se abordan en los siguientes capítulos experimentales. El tercer capítulo se centra en el desarrollo de un sistema de administración dirigida al Toll-like receptor 3 (TLR3), basado en nanopartículas mesoporosas de sílice funcionalizadas con el RNA sintético de doble cadena ácido polinosínico-policitidílico (poly(I:C)). El poly(I:C) ha mostrado efectos citotóxicos en diferentes tipos de cáncer, y los resultados obtenidos en este trabajo demuestran su capacidad de desencadenar respuestas apoptóticas en células de cáncer de mama, gracias a su interacción con TLR3. Asimismo, la carga del antibiótico antraciclínico doxorubicina en los mesoporos, ha permitido conseguir un efecto terapéutico aún más intenso. De hecho, se ha observado una mayor disminución de la viabilidad en la línea celular SK-BR3. El capítulo cuatro muestra el diseño de una estrategia de cooperación entre nanopartículas. El objetivo de este trabajo es el de mejorar la eficacia de la aproximación terapéutica para cáncer de mama desarrollada precedentemente, a través de la combinación de dos tipos de nanopartículas mesoporosas de sílice con puertas moleculares capaces de cooperar con el fin de conseguir un objetivo terapéutico. El primer tipo, de hecho, induce cambios que incrementan la interacción del segundo con la célula tumoral diana. Para ello, se han sintetizado nanopartículas cargadas con ácido 9-cis retinoico y funcionalizadas en su superficie con interferón-¿, y nanopartículas cargadas con el colorante sulforodamina B y con poly(I:C) anclado en superficie. Aprovechando la habilidad del interferón-¿ del ácido 9-cis retinoico de aumentar la expresión del TLR3, nuestra intención era la de mejorar la interacción de las nanopartículas funcionalizadas con poly(I:C) con las células diana. Los resultados obtenidos demuestran que la estrategia de combinación propuesta realmente ha producido un aumento de los niveles de internalización de los nanodispositivos funcionalizados con poly(I:C) en el modelo celular seleccionado. En el quinto capítulo se presenta un sistema basado en nanopartículas mesoporosas de sílice dendriméricas. El volumen de poro más amplio de este tipo de materiales hace de ellos unos dispositivos adecuados para lograr el objetivo principal de este proyecto: la administración local y la liberación controlada de moléculas de RNA pequeño de interferencia (siRNA) anti-factor de crecimiento vascular endotelial (VEGF) en células del epitelio pigmentado retinal. Los nanodispositivos se han sintetizado, cargado con siRNA y finalmente funcionalizado con cadenas de polietilenimina, que actúan de puerta molecular para la liberación controlada de las moléculas de siRNA y como agentes de escape endosomal para su liberación en el citosol. Los resultados obtenidos en el silenciamiento de VEGF en las células ARPE-19 resaltan el considerable potencial del sistema diseñado como transportador de siRNA. Las conclusiones generales en relación con los trabajos recopilados en esta tesis se resumen en el capítulo sei / [CA] La present tesi doctoral, titulada "Disseny i desenvolupament de nous nanodispositius amb portes biomoleculars per a l'alliberament dirigit i controlat de fàrmacs", està centrada en el disseny, síntesi, caracterització i avaluació in vitro de nous nanosistemes híbrids orgànics-inorgànics com a estratègies innovadores per a l'administració dirigida i controlada de molècules terapèutiques. El primer capítol d'aquest treball és una introducció general que defineix el context en el qual es situen els projectes duts a terme al llarg d'aquesta tesi. En particular, es descriu el concepte de nanomedicina, així com les principals estratègies per al desenvolupament de dispositius nanofarmacèutics eficients i els desafiaments que això comporta. A més, es presenten breument els materials mesoporosos de sílice. Successivament, es presenten els objectius generals que s'aborden en els següents capítols experimentals. El tercer capítol es centra en el desenvolupament d'un sistema d'administració dirigida al Toll-like receptor 3 (TLR3), basat en nanopartícules mesoporoses de sílice funcionalitzades amb l'RNA sintètic de doble cadena àcid polinosínic-policitidílic (poly(I:C)). El poly(I:C) ha mostrat efectes citotòxics en diferents tipus de càncer, i els resultats obtinguts en aquest treball demostren la seua capacitat de desencadenar respostes apoptòtiques en cèl·lules de càncer de mama, gràcies a la seua interacció amb TLR3. Així mateix, la càrrega de l'antibiòtic antraciclínic doxorubicina en els mesopors, ha permès aconseguir un efecte terapèutic encara més intens. De fet, s'ha observat una major disminució de la viabilitat en la línia cel·lular SK-BR3. El capítol quatre mostra el disseny d'una estratègia de cooperació entre nanopartícules. L'objectiu d'aquest treball és el de millorar l'eficàcia de l'aproximació terapèutica per a càncer de mama desenvolupada precedentment, mitjançant la combinació de dos tipus de nanopartícules mesoporoses de sílice amb portes moleculars capaces de cooperar amb la fi d'aconseguir un objectiu terapèutic. El primer tipus, de fet, indueix canvis que incrementen la interacció del segon amb la cèl·lula tumoral diana. Per a això, s'han sintetitzat nanopartícules carregades amb àcid 9-cis retinoic i funcionalitzades en la seua superfície amb interferó-¿, i nanopartícules carregades amb el colorant sulforodamina B i amb poly(I:C) ancorat en superfície. Aprofitant l'habilitat de l'interferó-¿ de l'àcid 9-cis retinoic d'augmentar l'expressió del TLR3, la nostra intenció era la de millorar la interacció de les nanopartícules funcionalitzades amb poly(I:C) amb les cèl·lules diana. Els resultats obtinguts demostren que l'estratègia de combinació proposada realment ha produït un augment dels nivells d'internalització dels nanodispositius funcionalitzats amb poly(I:C) en el model cel·lular seleccionat. El cinquè capítol presenta un sistema basat en nanopartícules mesoporoses de sílice dendrimèriques. El volum de porus més ampli d'aquest tipus de materials fa d'ells uns dispositius adequats per a aconseguir l'objectiu principal d'aquest projecte: l'administració local i l'alliberament controlat de molècules d'RNA xicotet d'interferència (siRNA) anti-factor de creixement vascular endotelial (VEGF) en cèl·lules de l'epiteli pigmentat retinal. Els nanodispositius s'han sintetitzat, carregats amb siRNA i finalment funcionalizats amb cadenes de polietilenimina, que actuen de porta molecular per a l'alliberament controlat de les molècules de siRNA i com a agents d'escap endosomal per al seu alliberament en el citosol. Els resultats obtinguts en el silenciament de VEGF en les cèl·lules ARPE-19 ressalten el considerable potencial del sistema dissenyat com a transportador de siRNA. Les conclusions generals en relació amb els treballs recopilats en aquesta tesi es resumeixen en el capítol sis. / [EN] The present PhD thesis, entitled "Design and development of new bio-gated nanodevices for targeted controlled drug release" is focused on the design, synthesis, characterization and in vitro evaluation of new hybrid organic-inorganic nanosystems as innovative strategies for the targeted and controlled delivery of therapeutic molecules. The first chapter of this work is a general introduction that defines the context in which the projects carried out during this thesis are placed. In particular, the concept of nanomedicine is described, as well as the main strategies for the development of efficient nanopharmaceutical devices and the related challenges. Furthermore, a brief presentation of mesoporous silica materials is given. Next, the general objectives that are addressed in the following experimental chapters are introduced. The third chapter is focused on the development of a targeting delivery system directed to Toll-like receptor 3 (TLR3) and based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA (dsRNA) polyinosinic-polycytidylic acid (poly(I:C)). Poly(I:C) has shown cytotoxic effects in different types of cancer, and the results obtained in this work demonstrate its ability to trigger apoptotic pathways in breast cancer cells, thanks to its interaction with TLR3. Furthermore, loading the mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent, allowed to achieve an enhanced therapeutic effect. In fact, a higher decrease of the cellular viability in SK-BR-3 cell line was observed. Chapter four shows the design of a nanoparticles cooperation strategy. The aim of this work is to improve the efficacy of the previously developed therapeutic approach for breast cancer through the combination of two gated mesoporous silica nanoparticles sets able to cooperate to achieve a medical goal. The first type, in fact, induces changes that enhance the interaction of the second one with the target cancer cell. In order to do that, nanoparticles loaded with 9-cis-retinoic acid and capped with interferon-¿, and nanoparticles loaded with sulforhodamine B dye and gated with poly(I:C) were synthesized. Taking advantage of the ability of both interferon-¿ and 9-cis-retinoic to increase TLR3 expression, we intended to improve the interaction of poly(I:C) functionalized nanoparticles with target cells. The obtained results show that the proposed combination strategy actually increased the uptake levels of poly(I:C) gated nanodevices in the cellular model selected. In the fifth chapter a system based on dendrimer-like mesoporous silica nanoparticles is presented. The higher pore volume of such materials makes them suitable for the achievement of the main aim of this project: the topical administration and controlled delivery of anti-vascular endothelial growth factor (VEGF) small interfering-RNA (siRNA) molecules to retinal pigmented epithelial cells. The nanodevices were synthesized, loaded with siRNA and finally functionalized with polyethylenimine chains, that act as molecular gate for the controlled release of the siRNA molecules and endosomal escape agent for cytosolic delivery. The obtained results in VEGF silencing in ARPE-19 cells highlight the noteworthy potential of the designed system as siRNA carrier. General conclusions regarding the works collected in this thesis are summarized in chapter six. / We thank the Spanish Government (projects SAF2010-21195 and MAT2012-38429-C04-01) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. A.U. and C.G. are grateful to the Ministry of Education, Culture and Sport for their doctoral fellowships. / Ultimo, A. (2019). Design and development of new bio-gated nanodevices for targeted controlled drug release [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129875 / Compendio

Yes / Understanding structure-property relationships is critical for the development of new drug delivery systems. This study investigates the properties of Pluronic smart hydrogel formulations for future use as injectable controlled drug carriers. The smart hydrogels promise to enhance patient compliance, decrease side effects and reduce dose and frequency. Pharmaceutically, these systems are attractive due to their unique sol-gel phase transition in the body, biocompatibility, safety and injectability as solutions before transforming into gel matrices at body temperature. We quantify the structural changes of F127 systems under controlled temperature after flow, as experienced during real bodily injection. Empirical formulae combining the coupled thermal and shear dependency are produced to aid future application of these systems. Induced structural transitions measured in-situ by small angle x-ray and neutron scattering reveal mixed oriented structures that can be exploited to tailor the drug release profile.

Des copolymères à blocs polylactide-poly(éthylène glycol) (PLA-PEG) ont été synthétisés par polymérisation par ouverture de cycle du L- ou D-lactide en présence de PEG mono- ou dihydroxylé. La masse molaire, la composition, la cristallisation et les propriétés thermiques des copolymères ont été caractérisées à l'aide de la DSC, NMR, GPC, etc. Des micelles biorésorbables ont été obtenues par la méthode dissolution directe sans utiliser de solvants organiques. Des mesures de tension de surface ont permis de déterminer la concentration micellaire critique des copolymères. Les résultats montrent que les micelles mélange L/D sont plus stables que les micelles seules en raison de l'effet stéréocomplexation entre les blocs L-PLA et D-PLA. Les comportements d'agrégation des micelles en milieu aqueux ont été étudiés en détail. Il apparaît que les micelles mélange présentent un nombre d'agrégation inférieur à celui des micelles seules. La dégradation hydrolytique des micelles a été étudiée dans les conditions in vitro. Le paclitaxel a été utilisé comme modèle de principes actifs pour évaluer les comportements in vitro et in vivo des micelles. Les méthodes dissolutio n directe et dialyse conduisent à des résultats comparables en ce qui concerne l'efficacité d'encapsulation et la teneur en principe actif. Les micelles mélange L/D présentent une meilleure capacité d'encapsulation que les micelles seules. Les expériences in vivo montrent que le paclitaxel est distribué dans tous les organes avec concentrations élevées après injection des micelles chargées. En comparaison avec la formulation clinique et les micelles par dialyse, les micelles chargées en paclitaxel par dissolution directe présentent un effet antitumeur plus important. / A series of polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers were synthesized by ring-opening polymerization of L- or D-lactide in the presence of mono- or dihydroxyl PEG. The molar mass, composition, crystallization and thermal properties were characterized by using DSC, NMR, GPC, etc. Bioresorbable micelles were obtained by direct dissolution method without using any organic solvents. Surface tension measurements were used to determine the critical micellar concentration of the copolymers. The results show that L/D mixed micelles are more stable than single ones due to strong stereocomplexation effect between L-PLA and D-PLA blocks. The aggregation behavior of micelles in aqueous medium was investigated in detail. It appears that mixed micelles present lower aggregation number than single ones. The hydrolytic degradation of the micelles was investigated under in vitro conditions. Paclitaxel was used as a model drug to investigate the in vitro and in vivo behavior of micelles as drug delivery system. The direct dissolution method yields comparable drug encapsulation efficiency and loading content as the traditional dialysis method. The drug encapsulation ability is higher for L/D mixed copolymer micelles than single micelles due to stereocomplexation. In vivo experiments show that paclitaxel is widely distributed and kept at high concentration levels in various tissues after administration of drug-loaded micelles. Compared with the current clinical formulation and micelles by dialysis, paclitaxel-loaded micelles by direct dissolution exhibit the highest antitumor ability.

Highly-exact structural characterization is the crucial step in the development and manufacturing process of pharmaceutical materials. Their structural composition is, however, often very complex and hardly identifiable. The eligible way for obtaining definite structural interpretation of these systems appears the high-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy. For this purpose the reliable tool - the ssNMR toolbox for comprehensive characterization of various pharmaceutical solids is described. The rigorous optimization of ssNMR techniques is carried out on enormous number of measured samples containing active pharmaceutical ingredients (APIs) with systems ranging from APIs formulated in solid dispersions to pure forms revealing extensive molecular disorder. In this study the influence of polymeric matrix on the creation of solid dispersion type susceptible for finely tuned controlled drug release is likewise discussed. The distinction between variable structural alignments of API molecules in 3D dimension of complicated pharmaceutical solids is allowed via simple strategy - factor analysis applied to hardly describable ssNMR spectra (13 C CP/MAS NMR and 19 F MAS NMR). The results of this ssNMR investigation contribute to better understanding of solid dispersion...

In der vorliegenden Arbeit wurden zwei neuartige biodegradierbare Nanopartikel (NP)-Typen definierter Größe auf ihre Eignung als Wirkstofftransporter für die Verwendung in der Photodynamischen Therapie (PDT) untersucht. Die Verwendung biodegradierbarer NP als Wirkstofftransporter in der PDT ist ein vielversprechender neuer Ansatz, der im Rahmen dieser Arbeit erstmalig untersucht wurde. Die in dieser Arbeit untersuchten NP bestehen aus humanem Serumalbumin (HSA), beziehungsweise Polylactid-co-Glycolid (PLGA) und wurden mit den Photosensibilisatoren (PS) Phäophorbid a (Pheo), Meta-Tetra (Hydroxy-Phenyl)- Porphyrin (mTHPP) oder Meta-Tetra (Hydroxy-Phenyl)-Chlorin (mTHPC) beladen. Es wurden die endozytotische Aufnahme, der lysosomale Abbau der NP und die intrazelluläre Freisetzung der PS in Abhängigkeit von der Inkubationszeit in vitro an humanen Krebszellen untersucht. Um die Effizienz der Photosensibilisierung durch die mit PS beladenen NP zu bestimmen, wurden die Phototoxizität und die intrazelluläre Singulettsauerstoffgenerierung bestimmt. Es konnte gezeigt werden, dass sowohl HSA- als auch PLGA-NP das Potential besitzen als Wirkstofftransporter in der PDT Verwendung zu finden. Insbesondere mTHPC-beladene NP wirken durch starke intrazelluläre Singulettsauerstoffgenerierung sehr phototoxisch. Die Experimente zeigen, dass die intrazelluläre PS-Konzentration geringeren Einfluss auf die Effizienz der Photosensibilisierung hat als die Freisetzung der PS und deren intrazelluläre Lokalisation. Die Biodegradierbarkeit von HSA und PLGA ermöglicht einen schnellen Abbau. Dadurch kann bereits bei sehr geringen intrazellulären PS-Konzentrationen hohe Phototoxizität erreicht werden. Der Fokus bei der Optimierung sollte einerseits in einer stabilen Verbindung zwischen PS und NP liegen, andererseits in einer effizienten Freisetzung nach der zellulären Aufnahme. Deshalb sind biodegradierbare Polymere sehr vielversprechende Materialien für die Entwicklung von PS-NP-Transportsystemen. / In the present study, two novel biodegradable nanoparticle (NP) types with a defined size were examined for their suitability as drug delivery systems for use in photodynamic therapy (PDT). NP drug transporters already found a successful application in chemotherapy but the use of biodegradable NP in PDT is a new promising challenge. The investigated NP consist of human serum albumin (HSA) and poly(lactic-co-glycolic acid) (PLGA) and were loaded with the photosensitizers (PS) pheophorbide a (Pheo), meta-tetra(hydroxy-phenyl)-porphyrin (mTHPP) or meta- tetra(hydroxy-phenyl)-chlorin(mTHPC). The endocytotic intracellular uptake and the time dependent drug release caused by decomposition of the biodegradable PS loaded nanoparticles were studied in vitro on Jurkat cells in suspension. The phototoxicity as well as the intracellular singlet oxygen generation was investigated for different incubation times. It was shown that both, HSA and PLGA NPs are promising carriers for PDT agents regarding uptake and phototoxicity. Especially the mTHPC loaded NPs show a very efficient phototoxicity caused by a very high singlet oxygen generation after the release of the PSs. The experiments show that the overall intracellular PS concentration is of less importance for the efficiency of the photosensitization compared to the amount of intracellular drug release and the intracellular localisation of the PS molecules. The biodegradability of the HSA and PLGA nanoparticles enables a fast intracellular drug release that causes high phototoxicity even for very low intracellular PS concentrations. Thus, the strategy for efficient PS loaded NP carriers is not a maximum loading. The main challenge is to create carriers with highly stable PS NP bonding to prevent any drug release before intracellular uptake combined with the ability of a complete drug release inside the target cells. Thus, biodegradable polymers are very promising materials for the design of NP-PS delivery systems