Yes / Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications. / This research was funded by a variety of sources, and the authors acknowledge the UK Engineering and Physical Sciences Research Council (EPSRC) National Productivity Investment Fund (NPIF) for a PhD Studentship for M.D.A. (Grant references: EP/R512564/1, 2065445), in support of the EPSRC First Grant for J.G.H. (Grant reference: EP/ R003823/1); the UK Royal Society for support of J.G.H. (Grant reference: RG160449); and the UK Royal Society and CONICET (Argentina) for supporting M.D.A., S.M., M.F.D., and J.G.H. (Grant Reference: A103355).

The effect of peptide charge on the self-assembly and gelation behaviour of three octa-peptides: VEVKVEVK (VEK2), VKVKVEVK (VEK3) and VEVEVKVE (VEK1) has been investigated and characterised. The critical gelation concentration of each peptide was found to correlate with the charge modulus carried by the peptide and to be independent of the sign of the charge. Hydrogels formed were found to be transparent and stable when the peptide charge modulus is > 1. No differences in hydrogel structure or mechanical properties, as probed by TEM and SAXS and shear rheology, were found when the peptides were at the same concentration and carried the same charge modulus. These peptides were shown to form dense fibrillar network formed by β-sheet rich single fibre which lateral aggregation is controlled by the peptide charge modulus. The increase in fibre lateral aggregation with decreasing charge modulus was found to correlate with the increase in hydrogel mechanical properties, showing that fibre lateral aggregation pays a key role in controlling the mechanical properties of these hydrogels. The release profiles from VEK1 and VEK3 at pH 7 of two hydrophilic model drug molecules, namely napthol yellow (NY) and martius yellow (MY) was analysed using UV-Vis spectrophotometry. The incorporation of the guest molecules did not affect the self-assembly of the peptide at a molecular level but did affect the level of lateral fibre aggregation observed and therefore the mechanical properties of the hydrogels. The release of each of the model compounds was monitored over time and shown to be controlled by Fickian diffusion. The guest molecule diffusion rate D was dependent on the ratio between the overall effective charges carried by the peptide, i.e.: the fibrillar network, and the overall charges carried by the guest molecules but independent from the hydrogel concentration and mechanical properties, in the concentration and guest loading range investigated. This work shows that the rate of release of small drug molecules can be manipulated, not only by changing the charges on the guest molecules, but also by manipulating the charged state of the self-assembling peptide molecule and through it the charge state of the fribrillar network. Furthermore the VEK3 system was conjugated to a series of thermo-responsive synthetic polymers which imparted a significant change in mechanical properties, assembled structures and release profiles upon heating. Observed changes when above the polymers LCST include increased mechanical strength, fibre thickening and increased diffusion coeffcients. The synthesis, and subsequent characterisation, of these materials is the first time responsive hydrogels of OEGMA copolymers has been reported.

Yes / The aim of this study was to design a controlled release vehicle for insulin to preserve its stability and biological activity during fabrication and release. A modified, double emulsion, solvent evaporation, technique using homogenisation force optimised entrapment efficiency of insulin into biodegradable nanoparticles (NP) prepared from poly (dl-lactic-co-glycolic acid) (PLGA) and its PEGylated diblock copolymers. Formulation parameters (type of polymer and its concentration, stabiliser concentration and volume of internal aqueous phase) and physicochemical characteristics (size, zeta potential, encapsulation efficiency, in vitro release profiles and in vitro stability) were investigated. In vivo insulin sensitivity was tested by diet-induced type II diabetic mice. Bioactivity of insulin was studied using Swiss TO mice with streptozotocin-induced type I diabetic profile. Insulin-loaded NP were spherical and negatively charged with an average diameter of 200–400 nm. Insulin encapsulation efficiency increased significantly with increasing ratio of co-polymeric PEG. The internal aqueous phase volume had a significant impact on encapsulation efficiency, initial burst release and NP size. Optimised insulin NP formulated from 10% PEG–PLGA retained insulin integrity in vitro, insulin sensitivity in vivo and induced a sustained hypoglycaemic effect from 3 h to 6 days in type I diabetic mice.

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.

No description available.

Made available in DSpace on 2014-06-11T19:31:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-11-27Bitstream added on 2014-06-13T19:20:14Z : No. of bitstreams: 1 peixoto_tp_dr_botfmvz.pdf: 7218430 bytes, checksum: 805d30dbbb4d65e7a3083c5277367671 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A proposta do presente trabalho foi a de comparar o tratamento convencional a base de colírio com o sistema de liberação controlada no tratamento de ceratites por Staphylococcus aureus por ciprofloxacina. Foram utilizados 20 coelhos, divididos em quatro grupos. Os grupos G1, G3 e G4 foram inoculados com 2,5μl da bactéria (108UFC) no estroma corneano. O grupo G2 não recebeu a aplicação do inóculo. O tratamento foi realizado com solução fisiológica para o grupo G1 (a cada seis horas por cinco dias), micropartículas de poli-lactatoco- glicolato (PLGA) contendo ciprofloxacina nos grupos G2 e G4, e colírio de ciprofloxacina no grupo G3 (a cada seis horas por cinco dias). Humor aquoso foi coletado no quinto dia de tratamento para análise por High-performance liquid chromatography (HPLC) da quantidade de ciprofloxacina na câmara anterior. As concentrações médias obtidas foram de 0,013μg/ml, 0,3μg/ml e 0,03μg/ml para os grupos G2, G3 e G4 respectivamente. Swab e biópsia da superfície ocular foram coletados para cultura no quinto dia de experimento. Apenas um animal do grupo G1 teve cultura positiva para S. aureus no material processado. Exame histopatológico revelou a presença bacteriana em todos os animais do grupo G1 e em dois animais do G3. Também foi constatado uma leve reação inflamatória no local da aplicação do sistema de liberação controlada. A análise dos dados mostrou que o tratamento com as micropartículas de PLGA foi eficaz no tratamento de ceratite bacteriana, eliminando completamente a presença de S. aureus e não sendo completamente biocompatível e biodegradável após cinco dias. / The proposal of this study was to compare the conventional treatment with eye drops with the controlled delivery system of PLGA, in the treatment of Staphylococcus aureus keratitis with ciprofloxacin. We used 20 rabbits, divided into four groups. The groups G1, G3 and G4 were inoculated with the bacterial 2.5μl (108UFC) in the corneal stroma. The G2 group did not receive the application of inoculum. The treatment was performed with basic saline solution in G1 (every six hours for five days), microparticles of poly-lactate co-glycolate (PLGA) containing ciprofloxacin in G2 and G4, and ciprofloxacin eye drops in group G3 (every six hours for five days). Aqueous humor was collected on the last day of treatment for analysis by High-performance liquid chromatography (HPLC) of the amount of ciprofloxacin in the anterior chamber. The average concentrations were obtained from 0013μg/ml, 0.3μg/ml and 0.03μg/ml for G2, G3 and G4 respectively. Swab and biopsy of the ocular surface were collected for culture on the fifth day of experiment. Only one animal in the G1 had positive culture for S. aureus in the processed material. Histological examination showed a bacterial presence in all animals of G1 and two animals of G3. It was also noted some light inflammatory reaction at the site of application of the controlled release. Data analysis showed that treatment with the microparticles of PLGA was effective in treating bacterial keratitis, completely eliminating the presence of S. aureus, not being completely biocompatible and biodegradable after five days.

Orientador: José Joaquim Titton Ranzani / Banca: Claudia Valeria S. Brandão / Banca: Georgia Nadalini Rodrigues / Banca: Renato Linhares Sampaio / Resumo: A proposta do presente trabalho foi a de comparar o tratamento convencional a base de colírio com o sistema de liberação controlada no tratamento de ceratites por Staphylococcus aureus por ciprofloxacina. Foram utilizados 20 coelhos, divididos em quatro grupos. Os grupos G1, G3 e G4 foram inoculados com 2,5μl da bactéria (108UFC) no estroma corneano. O grupo G2 não recebeu a aplicação do inóculo. O tratamento foi realizado com solução fisiológica para o grupo G1 (a cada seis horas por cinco dias), micropartículas de poli-lactatoco- glicolato (PLGA) contendo ciprofloxacina nos grupos G2 e G4, e colírio de ciprofloxacina no grupo G3 (a cada seis horas por cinco dias). Humor aquoso foi coletado no quinto dia de tratamento para análise por High-performance liquid chromatography (HPLC) da quantidade de ciprofloxacina na câmara anterior. As concentrações médias obtidas foram de 0,013μg/ml, 0,3μg/ml e 0,03μg/ml para os grupos G2, G3 e G4 respectivamente. Swab e biópsia da superfície ocular foram coletados para cultura no quinto dia de experimento. Apenas um animal do grupo G1 teve cultura positiva para S. aureus no material processado. Exame histopatológico revelou a presença bacteriana em todos os animais do grupo G1 e em dois animais do G3. Também foi constatado uma leve reação inflamatória no local da aplicação do sistema de liberação controlada. A análise dos dados mostrou que o tratamento com as micropartículas de PLGA foi eficaz no tratamento de ceratite bacteriana, eliminando completamente a presença de S. aureus e não sendo completamente biocompatível e biodegradável após cinco dias. / Abstract: The proposal of this study was to compare the conventional treatment with eye drops with the controlled delivery system of PLGA, in the treatment of Staphylococcus aureus keratitis with ciprofloxacin. We used 20 rabbits, divided into four groups. The groups G1, G3 and G4 were inoculated with the bacterial 2.5μl (108UFC) in the corneal stroma. The G2 group did not receive the application of inoculum. The treatment was performed with basic saline solution in G1 (every six hours for five days), microparticles of poly-lactate co-glycolate (PLGA) containing ciprofloxacin in G2 and G4, and ciprofloxacin eye drops in group G3 (every six hours for five days). Aqueous humor was collected on the last day of treatment for analysis by High-performance liquid chromatography (HPLC) of the amount of ciprofloxacin in the anterior chamber. The average concentrations were obtained from 0013μg/ml, 0.3μg/ml and 0.03μg/ml for G2, G3 and G4 respectively. Swab and biopsy of the ocular surface were collected for culture on the fifth day of experiment. Only one animal in the G1 had positive culture for S. aureus in the processed material. Histological examination showed a bacterial presence in all animals of G1 and two animals of G3. It was also noted some light inflammatory reaction at the site of application of the controlled release. Data analysis showed that treatment with the microparticles of PLGA was effective in treating bacterial keratitis, completely eliminating the presence of S. aureus, not being completely biocompatible and biodegradable after five days. / Doutor

Ce travail de thèse a pour objet la synthèse, la caractérisation et l’étude des propriétés de complexation de cages moléculaires riches en électrons, préparées selon une stratégie d’auto-assemblage dirigé par des métaux, ainsi que l’étude de leur aptitude à complexer ou libérer un substrat à l’aide d’un stimulus redox.Une présentation de la stratégie d’auto-assemblage dirigé par des métaux et de son efficacité pour l’élaboration de structures tridimensionnelles est d’abord proposée.Ce projet repose sur un travail préalable de synthèse de ligands riches en électrons, dérivés de l’unité tétrathiafulvalène (TTF) ou de son dérivé à système-pi étendu (ex TTF), motif dont les propriétés de donneurs pi sont bien établies. Plusieurs ligands tétra-topique sont ainsi été préparés et caractérisés.Les auto-assemblages discrets correspondant ont été obtenus par réaction avec divers complexes métalliques, donnant naissance à des cavités variées,contrôlées en termes de forme et de taille. Ces édifices ont été caractérisés par RMN (dont DOSY),spectrométrie de masse, le cas échéant par diffraction des rayons-X et leurs propriétés électrochimiques ont été étudiées par voltammétrie cyclique. Leur capacité à complexer des invités neutres ou ioniques a également été mise en évidence. Enfin, exploitant les caractéristiques géométriques et électroniques remarquables des dérivés à base ex TTF, l’aptitude de l’une des cages correspondantes à contrôler réversiblement le processus de libération/complexation d’un invité par oxydation/réduction chimique, a pu être démontrée. / This work is related to the synthesis and the characterization of electron-rich molecular cages, which are generated through a coordination-driven selfassembly strategy, as well as to the study of their ability to complex or release a substrate using a redox stimulus. A presentation of the metal-driven self-assembly methodology and of the corresponding efficiency in the preparation of three-dimensional structures is first proposed. This project is based on preliminary efforts in the design and the synthesis of electron-rich ligands, which are derived from the tetrathiafulvalene unit (TTF) or its piextended derivative (exTTF), whose pi-donating properties are well-established. Several tetratopic ligands were prepared and characterized. The corresponding discrete self-assemblies were obtained by reaction with various metal complexes, giving rise to various cavities whose shapes and sizes can be triggered. These structures were characterized by NMR (including DOSY), mass spectrometry, X-ray diffraction in some cases. Their electrochemical properties were studied by cyclic voltammetry. Their good binding properties for various neutral and ionic guests were also shown. Finally, exploiting the remarkable geometric and electronic features of exTTF derivatives, the ability of one of the corresponding cages to trigger reversibly the release/complexation process of a guest upon chemical oxidation/reduction, could be demonstrated

Die systemische Verabreichung von Amoxizillin/Metronidazol (AM) als Zusatz zu Scaling/Root planing (SRP) in der Behandlung der generalisierten Aggressiven Parodontitis (gAP) führt zu guten klinischen und mikrobiologischen Ergebnissen. Die lokale antiseptische Zusatzmedikation mit Chlorhexidin in einem Controlled-Delivery-Device (PerioChip, PC) verbessert das Ergebnis von SRP in der Behandlung der Chronischen Parodontitis. Die Anwendung in der Behandlung der gAP ist bisher noch nicht untersucht worden. Ziele: Der Effekt von PC als Zusatz zu SRP in der Therapie der gAP wurde untersucht. Die Wirksamkeit wurde mit der Standardmedikation AM verglichen. Neben klinischen Parametern wurde die Konzentration des Entzündungsmarkers Calprotectin in der Sulkusflüssigkeit (SF) bestimmt. Material/Methode: 36 gAP-Patienten (18/Gruppe, 35+/-4 Jahre) wurden mit SRP und randomisiert entweder mit AM oder PC behandelt. Zur Baseline, 3 und 6 Monate nach SRP wurden die klinischen Parameter PD, CAL, BoP, Pus erhoben sowie SF-Proben tiefer und flacher Referenzstellen entnommen. Die Calprotectin-Konzentration in der SF wurde mittels ELISA bestimmt. Ergebnisse: 3 Monate nach SRP zeigten beide Gruppen signifikante Verbesserungen der klinischen Parameter, wobei noch keine Unterschiede zwischen den Gruppen bestanden. Während die AM-Gruppe stabil blieb, verschlechterten sich mehrwurzelige Zähne und tiefe Referenzstellen der PC-Gruppe wieder signifikant. Nach 6 Monaten wies die AM-Gruppe signifikant mehr CAL-Gewinn und PD-Reduktion auf. Pus war nur noch in der PC-Gruppe nachweisbar. Die Calprotectin-Konzentration war zwar in beiden Gruppen signifikant gesunken, Unterschiede zwischen den Gruppen bestanden jedoch aufgrund hoher Standardabweichungen nicht. Schlussfolgerung: AM zeigte eine bessere klinische Wirksamkeit und Langzeitstabilität als PC. Aufgrund großer interindividueller Variabilität spiegelte die SF-Konzentration von Calprotectin die klinischen Unterschiede nicht wider. / Adjunctive systemic administration of amoxicillin/metronidazole (AM) in generalized aggressive periodontitis (gAP) therapy results in good clinical and microbiological outcome. Adjunctive use of chlorhexidine within a controlled-delivery-device (PerioChip, PC) improves the outcome of scaling/root planing (SRP) in chronic periodontitis therapy. Its effect in the treatment of gAP has not been evaluated. Aims: The effect of adjunctive use of PC in the treatment of gAP was investigated. Efficacy of PC was compared to the standard treatment with AM. Clinical parameters and the concentration of the inflammation marker calprotectin within gingival crevice fluid (GCF) were measured. Material/methods: 36 gAP patients (18/group, 35+/-4 years) were treated by SRP either AM or PC. Clinical parameters PD, CAL, BoP and Pus were recorded at baseline, 3 and 6 months after therapy. GCF was sampled at deep and shallow reference sites and the concentration of calprotectin was measured by ELISA. Results: Both groups showed significant improvements of clinical parameters 3 months after SRP, however differences between groups were not significant. While the AM-group remained clinically stable, multirooted teeth and deep reference sites of the PC-group showed significant deterioration again. 6 months after SRP, the AM-group showed significant more CAL gain and PD reduction. Pus was detectable in the PC group only. The concentration of calprotectin in GCF had significantly decreased in both groups; however differences between groups were not significant due to high standard deviations. Conclusion: AM showed higher efficacy in terms of clinical treatment outcome and long-term stability than PC. Due to high interindividual variability, GCF-concentrations of calprotectin failed to reflect clinical differences.

[ES] La presente tesis doctoral titulada "Reconocimiento de neurotransmisores basado en nanopartículas de oro y de sílice mesoporosa para aplicaciones de detección y liberación controlada" es una tesis realizada por compendio de artículos la cual se centra en el diseño, preparación, caracterización y evaluación de distintos nanodispositivos para la detección colorimétrica de neurotransmisores y sistemas de liberación controlada que responden a neurotransmisores basados en nanopartículas de oro y nanopartículas de sílice mesoporosa, equipadas con ligandos orgánicos, efectores enzimáticos, puertas moleculares y especies cromofluorogénicas o medicamentos. En el primer capítulo se introduce una visión general de lo que son los neurotransmisores, sus principales características y el importante papel que éstos desempeñan en el funcionamiento de nuestro organismo. Además, se presenta una descripción general de las propiedades y potenciales aplicaciones de las nanopartículas de oro funcionalizadas con ligandos orgánicos como sistemas de detección y las nanopartículas mesoporosas de sílice funcionalizadas con puertas moleculares como sistemas de liberación controlada. A continuación, en el segundo capítulo se presentan los objetivos generales que son abordados en los siguientes capítulos experimentales. En el tercer capítulo, se presentan tres sistemas de detección colorimétrica de neurotransmisores basados en la agregación de nanopartículas de oro doblemente funcionalizadas con ligandos orgánicos. El primer sistema es un sensor capaz de detectar de forma selectiva el neurotransmisor serotonina, utilizando nanopartículas de oro funcionalizadas con ditio-bis(propionato de succinimidilo) y N-Acetil-L-Cisteína. El segundo sistema consiste en un sensor para la detección selectiva del neurotransmisor norepinefrina diseñado a partir de nanopartículas de oro funcionalizadas con 4-(liponiloxi)benzaldehído y ácido 4-mercato fenilborónico. El tercer sistema está compuesto por nanopartículas de oro funcionalizadas con 4-(liponiloxi)benzaldehído y N-Acetil-L-Cisteína, para la detección de normetanefrina, un importante biomarcador del tumor feocromocitoma. Todos estos sistemas se evalúan en medios competitivos como suero sanguíneo u orina. En el cuarto capítulo se muestran dos sistemas de liberación controlados enzimáticamente basados en la apertura de puertas moleculares. El primer sistema de liberación controlada responde a la presencia del neurotransmisor acetilcolina. En concreto, se utilizan nanopartículas de sílice mesoporosa funcionalizadas en su superficie con grupos de ácido fenilborónico y tapadas con la enzima acetilcolinesterasa mediante la formación de ésteres cíclicos de ácido fenilborónico entre las cadenas de oligosacáridos de la enzima y los grupos fenilborónicos de la superficie de las nanopartículas. En este caso la reacción enzimática produce ácido acético que da lugar a la hidrolisis de los ésteres borónicos, destapando los poros y liberando la carga contenida en el interior. Además, se evalúa la capacidad del dispositivo diseñado para liberar el citotóxico doxorubicina en células cancerosas en presencia de acetiltiocolina. El segundo sistema consiste en un nanodispositivo para la liberación controlada en respuesta al neurotransmisor L-glutamato. Para esto se utilizan nanopartículas tipo Janus de oro-sílice mesoporosa funcionalizadas con la enzima L-glutamato oxidasa en la parte del oro y con una puerta molecular autoinmolante de arilboronato en la superficie de la sílice. La liberación controlada se basa en el reconocimiento del L-glutamato por la enzima L-glutamato oxidasa y la posterior formación de peróxido de hidrogeno, que es la especie que induce la escisión de la puerta autoinmolante y la subsecuente apertura de los poros. Finalment es mostra que el sistema dissenyat és capaç d'alliberar un fàrmac citotòxic en cèl·lules de càncer de cervell després de detectar la presència de L-glutamat. / [CA] La present tesi doctoral titulada "Reconeixement de neurotransmissors basat en nanopartícules d'or i de sílice mesoporosa per a aplicacions de detecció i alliberació controlada" és una tesi realitzada per compendi d'articles la qual se centra en el disseny, preparació, caracterització i avaluació de diferents nanodispositius per a la detecció colorimètrica de neurotransmissors i sistemes d'alliberació controlada que responen a neurotransmissors basats en nanopartícules d'or i nanopartícules de sílice mesoporosa equipades amb lligands orgànics, efectors enzimàtics, portes moleculars i espècies cromofluorogénicos o medicaments. En el primer capítol s'introdueix una visió general del que són els neurotransmissors, les seves principals característiques i l'important paper que aquests tenen en el funcionament del nostre organisme. A més es presenta una descripció general de les propietats i potencials aplicacions de les nanopartícules d'or funcionalitzades amb lligands orgànics com a sistemes de detecció, i de les nanopartícules mesoporoses de sílice funcionalitzades amb portes moleculars com a sistemes d'alliberament controlat. A continuació, en el segon capítol es presenten els objectius generals que són abordats en els següents capítols experimentals. En el tercer capítol, es presenten tres sistemes de detecció colorimètrica de neurotransmissors basats en l'agregació de nanopartícules d'or doblement funcionalitzades amb lligands orgànics. El primer sistema és un sensor capaç de detectar de forma selectiva el neurotransmissor serotonina, utilitzant nanopartícules d'or funcionalitzades amb ditiobis (propionat de succinimidilo) i N acetil-L-cisteïna. El segon sistema consisteix en un sensor per a la detecció selectiva de neurotransmissor norepinefrina dissenyat a partir de nanopartícules d'or funcionalitzades amb 4- (liponiloxi) benzaldehid i Àcid 4-mercatofenilborònic. El tercer sistema està compost per nanopartícules d'or funcionalitzades amb 4- (liponiloxi) benzaldehid i N acetil-L-cisteïna, per a la detecció de normatanefrina un important biomarcador del tumor feocromocitoma. Tots aquests sistemes s'avaluen en mitjans competitius com sèrum sanguini u orina. En el quart capítol es mostren dos sistemes d'alliberament controlats enzimàticament basats en l'obertura de portes moleculars. El primer sistema d'alliberament controlat respon a la presència del neurotransmissor acetilcolina. En concret, s'utilitzen nanopartícules de sílice mesoporosa funcionalitzades en la seva superfície amb grups d'àcid fenilborònic i tapades amb l'enzim acetilcolina esterasa mitjançant la formació d'èsters cíclics d'àcid fenilborònic entre les cadenes d'oligosacàrids de l'enzim i els grups fenilborónicos de la superfície de les nanopartícules. En aquest cas, la reacció enzimàtica produeix àcid acètic que dóna lloc a la hidròlisi dels èsters borònics, destapant els porus i alliberant la càrrega continguda a l'interior. A més, s'avalua la capacitat del dispositiu dissenyat per alliberar el citotòxic doxorubicina en cèl·lules canceroses en presència d'acetiltiocolina. El segon sistema consisteix en un nanodispositiu per alliberació controlada en resposta al neurotransmissor L-glutamat, per al que s'utilitzen nanopartícules tipus Janus d'or-sílice mesoporosa funcionalitzades amb l'enzim L-glutamat oxidasa en la part de l'or i amb una porta molecular autoimmolant d'arilboronat a la superfície de la sílice. La alliberació controlada es basa en el reconeixement de L-glutamat per l'enzim L-glutamat oxidasa i la posterior formació de peròxid d'hidrogen, que és l'espècie que indueix l'escissió de la porta autoimmolant i la subseqüent obertura dels porus. Finalment es mostra que el sistema dissenyat és capaç d'alliberar un fàrmac citotòxic en cèl·lules de càncer de cervell després de detectar la presència de L-glutamat. / [EN] This doctoral thesis entitled "Neurotransmitters recognition based on gold and mesoporous silica nanoparticles for sensing and controlled release applications" it is a thesis carried out by compendium of articles, which is focused on the design, preparation, characterization and evaluation of nanodevices for the colorimetric sensing of neurotransmitters and controlled delivery systems responsive to neurotransmitters, based on gold nanoparticles and mesoporous silica nanoparticles equipped with organic ligands, enzymatic effectors, molecular gates and chromo-fluorogenic species or drugs. The first chapter introduces an overview about what neurotransmitters are, their main characteristics and the important role they play in the functioning of our body. In addition, a general description of the properties and potential applications of gold nanoparticles functionalized with organic ligands as detection systems and mesoporous silica nanoparticles functionalized with molecular gates as controlled delivery systems is presented. In the second chapter, the general objectives that are addressed in the following experimental chapters are presented. In the third chapter, three colorimetric detection systems of neurotransmitters based on the aggregation of gold nanoparticles doubly functionalized with organic ligands are presented. The first system is a sensor capable of selectively detecting the neurotransmitter serotonin, using gold nanoparticles functionalized with dithio-bis(succinimidyl propionate) and N acetyl-L-cysteine. The second system consists of a sensor for the selective detection of the neurotransmitter norepinephrine designed from gold nanoparticles functionalized with 4- (liponyloxy)benzaldehyde and 4-mercaptophenylboronic acid. The third system is composed of gold nanoparticles functionalized with 4-(liponyloxy)benzaldehyde and N-Acetyl-L-Cysteine, for the detection of normetanephrine, an important biomarker of the pheochromocytoma tumor. All these systems are evaluated in competitive media such as blood serum or urine. In the fourth chapter, two enzymatic controlled delivery systems based on the opening of molecular gates are developed. The first controlled delivery system responds to the presence of the neurotransmitter acetylcholine. Specifically, it consists of mesoporous silica nanoparticles functionalized on their surface with phenylboronic acid groups and capped with the enzyme acetylcholinesterase, via the formation of cyclic phenylboronic acid esters between the oligosaccharide chains of the enzyme and the phenylboronic groups on the nanoparticles surface. In this case, the enzymatic reaction produces acetic acid that induces the hydrolysis of the boronic esters, uncapping the pores and releasing the entrapped payload. In addition, the ability of the nanodevice to release the cytotoxic doxorubicin in cancer cells in the presence of acetylthiocholine is evaluated. The second delivery system consists of a nanodevice responsive to the neurotransmitter L-glutamate. It is based on Janus gold-silica mesoporous nanoparticles functionalized with the enzyme L-glutamate oxidase in the gold part and with a self-immolative arylboronate molecular gate on the surface of the silica. Controlled delivery is based on the recognition of L-glutamate by the enzyme L-glutamate oxidase and the subsequent formation of hydrogen peroxide, which results in the cleavage of the self-immolative gate and the uncapping of the pores. Finally, it is shown that the designed system is capable of releasing a cytotoxic drug in brain cancer cells after detecting the presence of L-glutamate. / The authors acknowledge financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, MAT2015-64139-C4-4-R (MINECO/FEDER) and Project AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Projects PROMETEOII/2014/047 and PROMETEO/2018/024). T. Godoy-Reyes is grateful to Generalitat Valenciana for her Santiago Grisolía fellowship. A. García-Fernández is grateful to the Spanish Government for her FPU fellowship. A. Llopis-Lorente thanks “La Caixa” Foundation for his PhD grant. SCSIE (Universitat de València) is gratefully acknowledged for all the equipment employed. / Godoy Reyes, TM. (2020). Neurotransmitters recognition based on gold nanoparticles and mesoporous silica nanoparticles for sensing and controlled release applications [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/158420 / TESIS