Rozprawy doktorskie na temat „Mesoporous Materials - Drug Delivery -”

This study evolved to its last form primarily around the development of a hybrid material is the core of the work. This hybrid material is then further explored for two different applications which are catalysis and drug delivery. A nanoassembly was established around a mesoporous silica support. SBA-15 was picked as this support among the other mesoporous silica dueto its well-defined pore structure and accessible pore volume. The silica framework was doped with Zr-atoms and the pores partly infiltrated with Cu nanoparticles resulting in a hybrid material with tunable properties. SBA-15 was synthesized by a sol-gel method where a micellar solution was employed as a template for the silica framework. To achieve the doped version, a Zr precursor was added to the synthesis solution. The effects of different synthesis conditions on the final material were investigated. lt was observed that changes in these synthesis conditions yielded different particle morphology, pore size, and specific surface area. The infiltration method is based on functionalizing the (Zr-) SBA-15 support surfaces before the Cu ion attachment whereas EIWI is based on slow evaporation of the liquid from the (Zr-)SBA-15 - Cu aqueous suspension. Both methods are designed to yield preferential growth of Cu NPs in the pores with a diameter smaller than 1O nm and in oxidized form. However, depending on the infiltration method used different chemical states of the final material is achieved, i.e. Zr content and porous network properties are different. Cu-Zr-SBA-15 nanoassembl ies were used for the catalytic conversion of C02 into valuable fuels such as methanol and dimethyl ether (DME). The effect of different chemical states of the catalyst was investigated. lt was found that the Si precursor had a considerable impact on the overall performance of the catalyst whereas the Cu loading method (lnf or EIWI) changed the catalytic selectivity between DME and methanol. The activity of the catalyst was further investigated in a time-evolution study where the accumulation of each product in the gas phase and the molecular groups attached to the catalyst surface were recorded over time. Accordingly, thermodynamic equilibrium was achieved on the 14th day of the reaction under 250ºC and 33 bar. The resulting total C02 conversion was 24%, which is the thermodynamically highest possible conversion, according to theoretical calculations. lt was also concluded from the experimental results that, DME is formed by a combination of two methoxy surface groups . Additionally, the formation of DME also boosts the total C02 conversion to fuels, which otherwise is limited to 9.5%. The design of Cu-Zr-SBA-15 was also investigated for drug delivery applications, dueto its potential as a biomaterial, e.g. , a filler in dental composites, and the antibacterial properties of Cu. Also, the bioactivity of Si02 and Zr02 was considered to be an advantage . With this aim, Cu infiltrated Zr doped SBA-15 material was prepared by using TEOSas the silica precursor and the lnf-method to grow Cu NPs. The performance of the final material as a drug delivery vehicle was tested by an in-vitro delivery study with chlorhexidine digluconate. The nanoassemblies show a drug loading capacity of 25-40% [mg drug 1 mg (drug+carrier)] . The drug release was determined to be composed of two steps. The presence of Zr and Cu limits the burst release and beneficially slows down the drug release process. The effect of pore properties of SBA-15 was explored in a study where the antibiotic doxycycline hyclate was loaded in SBA-15 materials with different pore sizes. lt was observed that the pore size is directly proportional to the drug loading capacity [mg drug 1 mg (drug+carrier)] and the released drug % (the released drug amounUtotal amount of loaded drug). The release profile was fast, dueto its weak interactions with the SBA-15 and smaller size molecule compared to chlorhexidine digluconate.
Los sistemas de materiales híbridos poseen propiedades multifuncionales. En este trabajo se desarrolló un nanoensamblaje alrededor de un soporte de sílice mesoporoso. Como soporte se seleccionó SBA-15 debido a su estructura de poro bien definida y volumen de poro accesible. La matriz de sílice fue dopada con átomos de Zr y los poros se infiltraron parcialmente con nanopartículas de Cu dando como resultado un material híbrido con propiedades ajustables . La síntesis de SBA-15 se realizó mediante un método de sol-gel en el que se empleó una solución micelar como plantilla para el sílice. Para lograr la versión dopada, se añadió un precursor de Zr a la solución de síntesis. Se investigaron los efectos de diferentes condiciones de síntesis, como el catalizador así como la fuente de Si en las características del material final. Los cambios en estas condiciones de. síntesis dieron lugar a partículas con distinta morfología, tamaño de poro (11-15 nm) y área superficial específica (400-700 m2/g). Las nanopartículas de Cu (NP) se hicieron crecer en el sustrato (Zr-) SBA-15 usando los métodos de infiltración (lnf) o de impregnación húmeda inducida por evaporación (EIWI).Dependiendo del método de infiltración utilizado, se logran diferentes propieddes químicas del material final, es decir, el contenido de Zr y las propiedades de red porosa son diferentes. Los nanoensamblajes de Cu-Zr-SBA-15 producidos bajo diversas condiciones de síntesis se usaron para la conversión catalítica de C02 en combustibles valiosos tales como metanol y dimetil éter (DME). El precursor de Si (TEOS o SMS) tuvo un impacto considerable en el rendimiento global del catalizador mientras que el método de carga de Cu (lnf o EIWI) cambió la selectividad catalítica entre DME y metanol. Por otra parte, la actividad del catalizador se investigó evaluando la acumulación de cada producto en la fase gaseosa y los grupos moleculares unidos a la superficie del catalizador a lo largo del tiempo. Se llegó al equilibrio termodinámico en el día 14 de la reacción a 250 ºC y 33 bar. La conversión total resultante de C02 fue del 24%, que es la conversión termodinámicamente más alta posible, según los cálculos teóricos . El material híbrido sintetizado Cu-Zr-SBA-15 también se investigó para aplicaciones de administración de fármacos, debido a su potencial como material de relleno en compuestos dentales y las propiedades antibacterianas del Cu. Por otra parte, la bioactividad de SiO2 y ZrO2 podría ser ventajosa para esta aplicación. El rendimiento del material final como vehículo de administración de fármacos se probó mediante un estudio de liberación in vitro con digluconato de clorhexidina . Los materiales desarrollados muestran una elevada capacidad de carga de fármaco (25-40%). Los perfiles de liberación del fármaco muestran dos etapas: una primera etapa de liberación rápida de las moléculas del fármaco unidas con interacciones más débiles al sustrato mesoporoso, seguida por la difusión de las moléculas del fármaco que están unidas a la superficie del portador. La presencia de Zr y Cu limita la liberación inicial y reduce la velocidad de liberación del fármaco . En otro estudio se evaluó el efecto del tamaño de poro de SBA-15 en la liberación del antibiótico hiclato de doxiciclina. Se observó que el tamaño de poro es directamente proporcional a la capacidad de carga de fármaco, el porcentaje y la cantidad de fármaco liberado . En resumen, este trabajo demuestra el carácter multifuncional de una nanomatriz diseñada a medida que proporciona información valiosa para dos aplicaciones en catálisis y liberación de fármaco.
Hybridmaterial består av minst två komponenter, vilket ger dem mångfacetterade egenskaper. Detta har gjort att denna typ av material attraktiva sedan länge. Det är dock inte enkelt att tillverka dessa materialsystem. Ett enkelt och effektivt tillvägagångssätt behövs för att tillvara ta de önskade egenskaperna hos varje komponent och få dem att samverka. Denna avhandling bygger huvudsakligen på utvecklingen av ett hybridmaterial.Ett hybridmaterial med en sammansättning bestämd på nanonivå, tillverkades med mesoporös kiseldioxid, SBA-15, som stomme. SBA-15 valdes framför andra typer av mesoporös kiseldioxid på grund av dess väldefinierade porstruktur och stora, tillgängliga porvolym. Kiseldioxiden dopades med zirkoniumatomer och porerna fylldes delvis med kopparnanopartiklar, vilket resulterade i ett hybridmaterial med egenskaper som kunde varieras. SBA-15 tillverkades via en våtkemisk metod där en micellösning används som mall för kiseldioxidens struktur. Vid dopningen tillsätts en zirkoniumkälla till synteslösningen. Effekterna av olika tillverkningsparametrar, till exempel salter med katalytiska egenskaper (salter med F- eller Cl-), olika kiselkällor (tetraetyl ortosilikat eller natriummetasilikat), på materialens egenskaper studerades. Variationer av dessa parametrar ger material med olika form, porstorlekar (11 – 15 nm) och specifik yta (400 – 700 m2/g). Kopparnanopartiklar växtes i (Zr-)SBA-15-stommarna med två metoder: infiltration (Inf) eller indunstningsinducerad våtimpregnering (EIWI). Inf baseras på funktionalisering av (Zr-)SBA-15-stommen innan kopparjoner fick reagera med ytan. EIWI bygger på en blandning av (Zr-)SBA-15 och kopparsalt i en lösning där vätskan långsamt får avdunsta. Båda metoderna är designade för framställning av oxiderade kopparnanopartiklar, mindre än 10 nm i diameter, som ska växa i stommens porer. Dock påverkar infiltrationsmetoden den kemiska sammansättningen hos det slutliga materialet då Zr-koncentrationen och porositeten i stommen ändras. Cu-Zr-SBA-15-sammansättningar, tillverkade med varierande syntesparametrar, användes som katalysatorer för omvandling av CO2 till bränslen såsom metanol och dimetyleter (DME). Resultaten visar att valet av kiselkälla har en stor inverkan på katalysatorns prestanda, samt att metoden för att introducera koppar ändrar den katalytiska selektiviteten mellan DME och metanol. Katalysatorns aktivitet undersöktes även över tid. Ackumuleringen av varje produkt, både i gasfas och på katalysatorns yta, registrerades över tid. Termodynamisk jämvikt nåddes efter att reaktionen fortgått i fjorton dagar vid 250 °C och 33 bar. Den totala CO2-omvandlingen var 24 %, vilket, enligt teoretiska beräkningar, är den termodynamiskt högsta möjliga omvandlingen. Det observerades att DME bildas genom en kombination av två metoxygrupper på katalysatorns yta, samt att bildandet av DME ökar den totala omvandlingen av CO2 till bränsle, vilken annars är begränsad till 9.5 %. Cu-Zr-SBA-15-sammansättningen användes även i läkemedelstillämpningar. De kan användas som biomaterial, e.g., fyllnadsmaterial i tandkompositer, och koppar har antibakteriella egenskaper. Dessutom kan kiseldioxid och zirkoniumdioxid vara bioaktiva vilket ses som en fördel. För denna tillämpning tillverkades Cu-Zr-SBA-15 med TEOS som kiselkälla och Inf-metoden för att växa kopparnanopartiklar. Cu-Zr-SBA-15 lämplighet som bärare av läkemedelet klorhexidindiglukonat testades in vitro. I detta fall uppvisar bäraren en laddningskapacitet [massa laddat läkemedel/(massa laddat läkemedel +massa bärare)] på 25 – 40 %. Frisättningen av läkemedel skedde i två steg. Först frisattes en stor mängd läkemedelsmolekyler. Dessa var löst placerade i håligheter i de mesoporösa stommarna. Därefter frisattes läkemedel via diffusion av molekyler som bundit till stommens yta. De två stegen representerar växelverkan mellan läkemedel – läkemedel- och läkemedel – bärare. Närvaron av zirkonium och koppar begränsar den första frisättningen och förlänger den aktiva tiden, vilket är fördelaktigt ur tillämpningsperspektiv. Effekten av porstorlek hos SBA-15 vid läkemedelsfrisättning undersöktes också i en studie där SBA-15 fylldes med doxycyklinhyklat. Laddningskapaciteten och mängden frisatt läkemedel och andelen av laddat läkemedel som frisätts var båda direkt proportionella mot porstorleken där frisättningen av doxycyklinhyklat dominerades av läkemedel – läkemedelsväxelverkan. Doxycyklinhyklat är en mindre molekyl jämfört med klorhexidindiglukonat och växelverkar svagare med SBA-15 på grund av sin mer anjoniska natur. Sammanfattningsvis visar arbetet den multifunktionella karaktären hos en skräddarsydd nanosammansättning, vilket ger värdefulla insikter i två användningsområden: katalys och läkemedelstransport Materialet testas sedan i två olika tillämpningar: katalys och läkemedelstransport.

Parmi les récentes découvertes dans le monde des matériaux, les silices mésoporeuses ordonnées (SMO) ont suscité un intérêt considérable, notamment grâce à leurs perspectives d’application dans de nombreux domaines tels que le biomédical ou les technologies de séparation. Un tel engouement s’explique par la nature unique de leurs propriétés. En effet, les SMO possèdent en général de grandes surfaces spécifiques, de grands volumes poreux, des tailles de pores ajustables, des surfaces aisément modifiables, ainsi que des tailles et morphologies de particules adaptables. L’objectif principal de ce doctorat est donc d’utiliser au mieux ces propriétés pour synthétiser et caractériser de nouveaux systèmes ayant un potentiel d’application en imagerie par résonnance magnétique (IRM) et en relargage contrôlé de médicaments par voie orale. Les premières et secondes parties de ce travail (chapitres 4 et 5) portent sur l’étude des paramètres de synthèse des SMO de type SBA-15 et KIT-6 ainsi que sur leurs effets sur les propriétés poreuses obtenues après calcination. Les résultats présentés montrent toute l’importance de bien contrôler cette porosité afin de caractériser correctement les différentes structures et topologies poreuses accessibles. La troisième et la quatrième partie de cette thèse (chapitres 6 et 7) visent à concevoir et évaluer le potentiel de nouveaux agents de contraste (AC) positifs pour l’IRM basés sur des nanoparticules (Nps) de MCM-41 et MCM-48 fonctionnalisées avec des ions paramagnétiques tels que le gadolinium (Gd) ou le manganèse (Mn). Les résultats de ces études démontrent la supériorité des réseaux poreux 3-D comme supports pour l’insertion d’atomes paramagnétiques, utilisés pour bonifier le signal en IRM. Les Nps de MCM-48 dopées avec du Gd ou du Mn améliorent significativement la relaxivité des protons d’hydrogène dans l’eau tout en conservant un rapport r2/r1 proche de l’unité (1.5 – 2), confirmant leur performance en tant qu’AC positifs. Par ailleurs, l’utilisation de nombreuses techniques de caractérisation et de tests in vitro ont permis de délimiter clairement le potentiel effectif ainsi que les limitations de ces Nps pour des études de traçage cellulaire. La dernière partie de ce travail (chapitre 8) se concentre sur le greffage d’une protéine succinylée, la β-lactoglobuline, sur des Nps de MCM-48 fonctionnalisées afin de développer une nouvelle plateforme de relargage contrôlé de médicaments par voie orale. Les résultats obtenus avec ce système nano-conjugué et nutraceutique montrent un bon contrôle du relargage en fonction du pH ainsi qu’une bonne biocompatibilité et une excellente stabilité colloïdale dans un milieu physiologique. L’utilisation de cette protéine bon marché représente une alternative potentielle à l’utilisation des bio-polymères classiques.
Among recent discoveries in material science, ordered mesoporous silica (OMS) have been in the limelight and attracted considerable attention because of their prospects of application, especially in the biomedical field and separation technologies. Such growing interest is explained by their unique physico-chemical properties. Indeed, OMS usually exhibit high specific surface areas, high pore volumes, adjustable pore sizes, ease of surface functionalization and customizable particle size and shape. The main objective of this Ph.D. thesis is to use these properties in order to design and characterize novel systems with potential applications in magnetic resonance imaging (MRI) and/or oral drug delivery. The first and second parts of this project (chapters 4 and 5) deal with SBA-15 and KIT-6 materials and the effects of the different synthesis parameters on the porosity features of the structures, obtained after calcination. The results showed that it is of prime interest to thoroughly and accurately characterize the porosity of these silicas in order to correctly assess their porous topologies. Such knowledge could be of substantial importance for high-tech applications of OMS. The third and fourth part of this thesis (chapters 6 and 7) are aimed to design, characterize and evaluate the potential of novel positive contrast agents (CA) for MRI based on MCM-41 and MCM-48 nanoparticles (Nps) functionalized with paramagnetic ions such as gadolinium (Gd) or manganese (Mn). The results reported in these studies demonstrate the superiority of 3-D pore networks as a host for the insertion of paramagnetic atoms used to enhance the signal in MRI. Also Gd and Mn loaded MCM-48 Nps provide a significant increase in 1H proton longitudinal relaxivity while maintaining low r2/r1 ratio (1.5 – 2) in water. Furthermore, various modern techniques and in vitro tests were used to clearly delineate the true potential and limitations of these inorganic contrast agents for cellular and in vivo tracking studies. The last part of this work (chapter 8) is focused on the binding of a succinylated protein, the β-lactoglobulin, onto functionalized MCM-48 Nps for the development of a new oral drug delivery platform. This nutraceutical nano-conjugate system reveals promising features such as high biocompatibility, efficient pH-responsive properties for both hydrophilic and hydrophobic drugs/dyes and excellent colloidal stability. The use of this low-cost protein could represent an alternative over classical biopolymers.

A range of mesoporous materials based on SBA-15, KIT-6 and FDU-12 have been prepared using neutral block copolymers Pluronic P123 and F127 and characterised using methods including electron microscopy and nitrogen adsorption. Typically the materials have a hexagonal (p6mm) or cubic (Fm3m and Ia-3d) symmetry and pore geometry and are rendered porous by either calcination or solvent extraction. Organic functional groups were incorporated into the silica walls of the materials by co-condensation in the form of propyl thiols and additives in the form of alkanes were added to control pore size and geometry. The effects of temperature, additives, organic functionalisation, synthesis time and sol-gel composition were investigated and the resulting materials were tested as supports for protein adsorption, enzyme immobilisation, and drug delivery. Two FDU-12 materials of differing entrance and cavity sizes were used to adsorb a range of proteins with molecular weight 17 to 160 kDa to determine if there was a size exclusion effect. It was seen that the larger pore material was able to adsorb proteins of a larger size (molecular weight 105 kDa) and an exclusion effect was observed when the dimension of the proteins became too great (larger than 130 kDa). There was no clear trend for the smaller pore material where each protein was adsorbed to some extent by the material but apart from the smallest protein, myoglobin, mainly on the surface and not within the pores. The adsorption of the lipase B from Candida Antartica, CALB, was studied on a range of mesoporous supports with their templates removed by either calcination or extraction. The effect of pore size and functionalisation was investigated in terms of maximum loading and rate of loading. By functionalising the KIT-6 material the maximum loading of CALB was reduced from 45.5 to 32 mg/g whereas functionalising the FDU-12 material increased the maximum from 33 to 42.5 mg/g. The activity of the immobilised CALB was measured by enantioselective transesterification of (R)-1-phenylethanol in methyltetrabutyl ether (MTBE). The effect of loading, surface functionalisation and reusability in organic media were investigated. Functionalisation with propyl thiol was seen to increase the rate of conversion after 30 minutes for both KIT-6 and FDU-12 materials. Selected FDU-12 and KIT-6 materials with window sizes from 6 to 12 nm and with and without functionalisation were used to carry out a drug release study using Bovine serum albumin (BSA). BSA was loaded onto the material and the uptake quantified using nitrogen adsorption, elemental analysis, and thermogravimetric analysis. The release of BSA into simulated body fluid at 37 ºC was measured using HPLC. Functionalisation was seen to have little effect. The type of cubic morphology controlled the rate at which the BSA was released. The KIT-6 3D channel material exhibited a burst release initially followed by a steady release of BSA whereas the mesocage FDU-12 material had a slower and more linear release profile, closer to that desired.

The aim of this PhD work was to develop and characterize all physicochemical aspects of this new CRT for CTZ and AKS using OMS until the introduction onto the market. The first part comprehends the characterization of different OMS synthesized and commercially available; the study of different incorporation techniques based on hydrophilicity/hydrophobicity of API; the characterization of the new impregnated OMS. Consequently, the work is oriented on the interaction details of API on silica surfaces. A closer look is given to the big questions of OMS-drug phenomena: mobility, solubility, bioavailability, etc. Therefore, all the scCO2 incorporation parameters have been studied, highlighting the differences between OMS and the spatial assembly of drug inside the mesoporous channels. Thus, the patented CRT has been developed for AKS describing all the main aspect of the innovative semisolid formulation. In-vitro and ex-vivo release test has been produced and characterized, revealing the functionality of the OMS reservoir effect. Finally, the same DDS have been developed for CTZ. Both the DDS have been compared with commercially available creams.

A literature review of medical implant applications of mesoporous silica films was written, highlighting the advantages and limitations of different film synthesis methods. Both films synthesized through the EISA sol-gel method and particulate films, including those synthesized through the direct growth method, were reviewed and discussed. All films were found to have their strengths and weaknesses, however, the films synthesized through the direct growth method was found to be the most promising type for coating implants. In addition to the literature review, copper-doped mesoporous silica films were synthesized on titanium grade 2 substrates. SEM shows that particles grown on all the films and EDX elemental analysis confirms the presence of copper in the material. Nitrogen physisorption measurements show that particles with incorporated copper have a higher specific surface area, and pore volume compared to un-doped particles. No copper content could be confirmed through FTIR. The particles grown on titanium substrates were more rod-like compared to the ones grown on the silicon substrates as control.

The idea of utilizing nanomaterials in bio-related applications has been extensively practiced during the recent decades. Magnetic nanoparticles (MPs), especially superparamagnetic iron oxide nanoparticles have been demonstrated as promising candidates for biomedicine. A protective coating process with biocompatible materials is commonly performed on MPs to further enhance their colloidal and chemical stability in the physiological environment. Mesoporous hollow silica is another class of important nanomaterials that are extensively studied in drug delivery area for their ability to carry significant amount of guest molecules and release in a controlled manner. In this study, different synthetic approaches that are able to produce hybrid nanomaterials, constituting both mesoporous hollow silica and magnetite nanoparticles, are described. In a two-step approach, pre-synthesized magnetite nanoparticles are either covalently conjugated to the surface of polystyrene beads and coated with silica or embedded/enclosed in the porous shell during a nanosized CaCO3 templated condensation of silica precursors, followed by acid dissolution to generate the hollow structure. It was demonstrated that the hollow interior is able to load large amount of hydrophobic drugs such as ibuprofen while the mesoporous shell is capable of prolonged drug. In order to simplify the fabrication procedure, a novel in-situ method is developed to coat silica surface with magnetite nanoparticles. By refluxing the iron precursor with mesoporous hollow silica nanospheres in polyamine/polyalcohol mixed media, one is able to directly form a high density layer of magnetite nanoparticles on silica surface during the synthesis, leaving reactive amine groups for further surface functionalization such as fluorescence conjugation. This approach provides a convenient synthesis for silica nanostructures with promising potential for drug delivery and multimodal imaging. In addition to nanoparticles, nanowires also benefit the research and development of instruments in clinical diagnosis. Semiconductive nanowires have demonstrated their advantage in the fabrication of lab-on-a-chip devices to detect many charge carrying molecules such as antibody and DNA. In our study, In2O3 and silicon nanowire based field effect transistors were fabricated through bottom-up and top-down approaches, respectively, for ultrasensitive bio- detection of toxins such as ricin. The specific binding and non-specific interaction of nanowires with antibodies were also investigated.

[EN] The present PhD thesis, which is entitled "Design of new bio-gated nanodevices for advanced communication processes and targeted controlled release of therapeutic agents" is focused on the development of new functional hybrid organic-inorganic materials for applications in the field of the controlled delivery of target molecules. The first chapter of the present thesis gives an introduction to the organic-inorganic hybrid materials functionalized with "molecular gates" and its application in controlled release processes. The second chapter of this thesis is focused on the development of a new nanodevice able to deliver its cargo as a function of the glucose concentration. The nanodevice is based on mesoporous silica nanoparticles loaded with a suitable fluorophore and functionalized with propylbenzymidazole moieties on the pore outlets. The mesopores are then capped with an active cyclodextrin modified glucose oxidase enzyme (through the formation of an inclusion complex between the cyclodextrins and the propylbenzymidazole group anchored to the solid support). When glucose is added its enzymatic oxidation produced gluconic acid. This acid induced a decrease in the pH of the medium and the protonation of the benzymidazole group that might result in the inclusion complex dethreading and the subsequent cargo release. The third chapter of the thesis is focused on the development of a new redox-responsive material for the controlled delivery of cytotoxic drugs in cancer cells. The system is based on mesoporous silica nanoparticles loaded with a reporter (safranin O) and functionalized with two different sized polyethylene glycol chains in the pore outlets using a disulfide linkage. In presence of glutathione, the disulfide bonds are cleaved allowing the release of the entrapped cargo. Once confirmed the aperture protocol, the uptake of the gated nanoparticles and their ability to deliver the cargo (fluorophore or cytotoxic agent) in HeLa cells were tested. Moreover, cell viability assays were also performed. The fourth chapter of the thesis is focused on the preparation and the study of a nanodevice for the controlled delivery in senescent cells in a murine model of pulmonary fibrosis. The material is prepared using mesoporous silica nanoparticles (as an inorganic support) and galactoligosaccharide (molecular gate) moieties anchored on the external surface. In presence of senescent cells, which overexpress ß-galactosidase enzyme, the hydrolysis of the galactooligosaccharide capping molecules take place and the cargo release from the inner of the pores is produced (rhodamine B). After the in vitro studies, the ability of nanoparticles to accumulate and release their payload in tissues with abundance of senescent cells was evaluated in vivo. For that purpose, mice with induced pulmonary fibrosis, pathogenesis with associated increased alveolar senescence, were treated with the synthesized material and subsequently examined to assess its ability to accumulate and release its payload (fluorophore) in lung's damaged areas. In the fifth chapter of the thesis it has been explored the concept of cascade chemical communication using different types of nanodevices, each of them loaded with a certain messenger and externally functionalized with a gate-like entity that controls the release of the payload. When the enzyme able to hydrolyze the molecular gate that blocks the pores of the first type of nanoparticles (S1), is added to an aqueous suspension containing the three nanoparticles, the delivery of the chemical messenger 1 is produced. This messenger is able to open the second type of nanoparticles (S2) which delivers the messenger 2. Finally, the messenger 2 triggers the aperture of the third group of gated system (S3), which ultimately delivers its load (a dye) as a final response.
[ES] La presente tesis doctoral titulada "Diseño de nuevos nanodispositivos para procesos avanzados de comunicación y liberación controlada y dirigida de agentes terapéuticos" está centrada en el desarrollo de nuevos materiales híbridos orgánico-inorgánicos funcionales para aplicaciones en el campo de la liberación controlada de moléculas de interés. El primer capítulo de la tesis ofrece una introducción a los materiales híbridos orgánico-inorgánicos funcionalizados con "puertas moleculares" y su aplicación en procesos de liberación controlada. En el segundo capítulo de la tesis se aborda el desarrollo de un nanodispositivo capaz de responder y liberar su carga en función de la concentración de glucosa. Este nanodispositivo está basado en nanoparticulas de sílice mesoporosa funcionalizadas en su superficie externa con grupos benzimidazol y con los poros cargados con un fluoróforo. Los poros se cierran al añadir la enzima glucosa oxidasa funcionalizada con ciclodextrinas (por formación de un complejo de inclusión entre el benzimidazol y los oligosacáridos cíclicos). Al adicionar glucosa se produce su oxidación enzimática dando ácido glucónico. Este ácido induce una bajada del pH del medio con la consiguiente protonación de los benzimidazoles y la ruptura de los complejos de inclusión. Esta ruptura provoca la salida de la enzima de la superficie y la liberación del colorante atrapado en los poros. El tercer capítulo de la tesis se ha centrado en el desarrollo de un material para la liberación controlada de agentes citotóxicos en células cancerosas en respuesta a cambios en el potencial redox. De nuevo se emplean nanopartículas de sílice mesoporosa con los poros cargados con un colorante (safranina O) y la superficie externa funcionalizada con dos polietilenglicoles conteniendo enlaces disulfuro. En presencia de glutatión se produce la reducción del enlace disulfuro con la consiguiente liberación del colorante. Una vez confirmado el protocolo de apertura, se estudió la internalización y la liberación de un fluoróforo y de un agente citotóxico en el modelo celular HeLa, realizando además ensayos de viabilidad. En el cuarto capítulo de la tesis se ha preparado y ensayado un nanodispositivo para la liberación controlada en células senescentes en un modelo murino de fibrosis pulmonar. El material se prepara empleando nanopartículas de sílice mesoporosa y un galactooligosacárido anclado en la superficie externa. En presencia de células senescentes, que sobreexpresan la enzima ¿-galactosidasa, se produce la hidrólisis del oligosacárido con la consiguiente liberación de la carga atrapada en los poros del soporte (rodamina B). Tras los estudios in vitro, la capacidad del nanodispositivo de acumularse y liberar su carga en tejidos ricos en células senescentes se evaluó in vivo. Para ello, ratones con fibrosis pulmonar inducida, patología en la que se ha descrito la aparición de senescencia, se trataron con el material sintetizado y posteriormente fueron examinados para comprobar la capacidad de acumularse y liberar su carga (fluoróforo) en la zona pulmonar dañada. En el quinto capítulo se ha explorado el proceso de comunicación química en cascada empleando tres tipos de nanopartículas mesoporosas de sílice cargadas con diferentes mensajeros y funcionalizadas con tres puertas moleculares distintas. Cuando sobre una suspensión de las tres nanopartículas se añade la enzima capaz de hidrolizar la puerta molecular que bloquea los poros del primer tipo de nanopartículas (S1), se produce la liberación del mensajero 1. Este mensajero es capaz de inducir la apertura del segundo tipo de nanopartículas (S2), que a su vez liberan al medio el mensajero 2. Por último, el mensajero 2 es capaz de abrir la puerta molecular del tercer tipo de nanopartículas (S3), que liberan finalmente su carga (un colorante) como respuesta final.
[CAT] La present tesis doctoral titulada "Disseny de nous nanodispositius per a processos avançats de comunicació i lliberació controlada i dirigida d'agents terapèutics" està centrada en el desenvolupament de nous materials híbrids orgànic-inorgànic funcionals per a aplicacions en el camp de la lliberació controlada de molècules d'interès. El primer capítol de la tesis ofereix una introducció als materials híbrids orgànic-inorgànic funcionalitzats amb "portes moleculars" i la seua aplicació en processos de lliberació controlada. En el segon capítol de la tesis s'aborda el desenvolupament d'un nanodispositiu capaç de respondre i lliberar la seua càrrega en funció de la concentració de glucosa. Este nanodispositiu està basat en nanopartícules de sílice mesoporoses funcionalitzades a la seua superfície externa amb grups benzimidazol i amb els pors carregats amb un fluoròfor. Els pors queden bloquejats al afegir el enzim glucosa oxidasa funcionalitzada amb ciclodextrines (per formació d'un complex d'inclusió entre el benzimidazol i els oligosacàrids cíclics). Al afegir glucosa es produeix la seua oxidació enzimàtica donant lloc a àcid glucònic. Este àcid indueix una baixada del pH del medi amb la consegüent protonació dels benzimidazols i el trencament dels complexes d'inclusió. Este trencament provoca l'eixida del enzim de la superfície i la lliberació del colorant atrapat als pors. El tercer capítol de la tesis s'ha centrat en la preparació d'un material per a la lliberació controlada d'agents citotòxics en cèl¿lules canceroses en resposta a canvis en el potencia redox. De nou s'empren nanopartícules de sílice mesoporoses amb els pors carregats amb un colorant (safranina O) i la superfície externa funcionalitzada amb dos polietilenglicols (de diferent pes molecular) contenint enllaços disulfur. En presència de glutatió es produeix la reducció del enllaç disulfur amb la consegüent lliberació del colorant. Una volta confirmat el protocol d'obertura, es va estudiar la internalització i la lliberació d'un fluoròfor i d'un agent citotòxic en el model cel¿lular HeLa, realitzant ademés assajos de viabilitat. En el quart capítol de la tesis s'ha preparat i s'ha estudiat un nanodispositiu per a la lliberació controlada en cèl¿lules senescents, en un model murí de fibrosis pulmonar. El material es prepara emprant nanopartícules de sílice mesoporoses i un galactooligosacàrid anclat a la superfície externa del material. En presència de cèl¿lules senescents, que sobreexpresen el enzim ¿-galactosidasa, es produeix la hidròlisis del oligosacàrid amb el consegüent alliberament de la càrrega atrapada en els pors del suport (rodamina B). Després dels estudis in vitro, la capacitat del nanodispositiu d'acumular-se i lliberar la càrrega en teixits rics en cèl¿lules senecents es va evaluar in vivo. Amb este propòsit, ratolins amb fibrosis pulmonar induïda, patologia en la que s'ha descrit l'aparició de senescència en els teixits danyats, es van tractar amb el material sintetitzat i posteriorment van ser examinats per a comprovar la capacitat d'acumular-se i lliberar la seua càrrega (fluoròfor) en la zona dels pulmons afectada. En el quint capítol s'ha explorat el procés de comunicació química en cascada utilitzant tres tipus de nanopartícules mesoporoses de sílice carregades amb diferents missatgers i funcionalitzades amb tres portes moleculars diferents. Quan, sobre una suspensió de les tres nanopartícules, s'afegeix l'enzim capaç d'hidrolitzar la porta molecular que bloqueja els pors del primer tipus de nanopartícules (S1), es produeix la lliberació del missatger 1 des de S1. Este missatger és capaç d'induir l'obertura del segon tipus de nanopartícules (S2), les quals lliberen al medi el missatger 2. Per últim, el missatger 2 és capaç d'obrir la porta molecular del tercer tipus de nanopartícules (S3), que lliberen finalment la seua càrr
Giménez Morales, C. (2016). Design of new bio-gated nanodevices for advanced communication processes and targeted controlled release of therapeutic agents [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62822
TESIS

La presente tesis doctoral, titulada "Nanotecnología y química supramolecular en procesos de liberación controlada y reconocimiento molecular para aplicaciones biomédicas", se centra en dos temas importantes: el reconocimiento molecular y los procesos de liberación controlada. Esta tesis doctoral está estructurada en cuatro capítulos. El primer capítulo introduce el concepto de materiales híbridos orgánicos-inorgánicos funcionalizados con puertas moleculares y sus aplicaciones biomédicas como nanomateriales para dirigir y controlar la liberación controlada de fármacos. Además se introduce una breve descripción sobre sensors colorimétricos basados en la base de la quimica supramolecular, particularmente en los procesos de reconocimiento molecular. En particular, el capítulo 2 describe la preparacion de cinco nanodispositivos que responden a enzimas. Estos materiales híbridos se componen de dos unidades principales: un soporte mesoporoso basado en sílice inorgánica, capaz de encapsular moléculas orgánicas y un compuesto orgánico anclado en la superficie externa del soporte mesoporoso inorgánico que actúa como puerta molecular. Todos los sistemas propuestos utilizan puertas moleculares peptídicas que responden a temperatura o enzimas como estímulo. La segunda parte de esta tesis doctoral se centra en el diseño y desarrollo de un nuevo compuesto químico capaz de detectar monóxido de carbono in vivo. En resumen, para todos los resultados antes mencionados podemos decir que esta tesis doctoral constituye una contribución científica original al desarrollo de la química supramolecular. Sus resultados derivados de los estudios presentados dejan rutas abiertas para continuar el estudio y el desarrollo de nuevos materiales híbridos y sensors químicos más eficientes para aplicaciones biomédicas y terapeuticas.
This PhD thesis entitled "Nanotechnology and supramolecular chemistry in controlled release and molecular recognition processes for biomedical applications", is focused on two important subjects: molecular recognition and controlled delivery processes. This PhD thesis is structured in four chapters. The first chapter introduces the concept of organic-inorganic hybrid materials containing switchable "gate-like" ensembles and their biomedical applications as nanomaterials for targeting and control drug delivery. Furthermore, is introduced a short review about chromo-fluorogenic chemosensors based on basic principles of supramolecular chemistry, particulary in molecular recognition processes. In particular, in chapter 2 is focus on the development of enzymatic-driven nanodevices. These hybrid materials are composed of two main units: an inorganic silica based mesoporous scaffold, able to store organic molecules and an organic compound anchored on the external surface of the inorganic mesoporous support than acts as molecular gate. All the systems proposed use peptidic gates that respond to temperature or enzimatic stimulis. The second part of this PhD thesis is focused on the design and development of a new chemical compound capable of detecting carbon monoxide in vivo. In summary, for all the results above mentioned we can say that this PhD thesis constitutes an original scientific contribution to the development of supramolecular chemistry. Its results derived from the studies presented leaves open routes to continue the study and development of new hybrid materials and more efficient chemical sensors with biomedical and therapeutic applications.
La present tesi doctoral, titulada "Nanotecnologia i química supramolecular en processos d'alliberament controlat i reconeixement molecular per a aplicacions biomèdiques", es centra en dos temes importants de la química: el reconeixement molecular i els processos d'alliberament controlat. Aquesta tesi doctoral està estructurada en quatre capítols. El primer capítol introdueix el concepte de materials híbrids orgànics-inorgànics funcionalitzats amb portes moleculars i les seves aplicacions biomèdiques com nanomaterials per dirigir i controlar l'alliberament controlat de fàrmacs. A més s'introdueix una breu descripció sobre sensors colorimètrics fonamentats en la base de la química supramolecular, particularment en els processos de reconeixement molecular. En particular, el capítol 2 descriu la preparació de cinc nanodispositius que responen a enzims. Aquests materials híbrids es componen de dues unitats principals: un suport mesoporos basat en sílice inorgànica, capaç d'encapsular molècules orgàniques i un compost orgànic ancorat a la superfície externa del suport mesoporós inorgànic que actua com a porta molecular. La segona part d'aquesta tesi doctoral es centra en el disseny i desenvolupaent d'un nou compost químic capaç de detectar monòxid de carboni in vivo. En resum, per a tots els resultats abans mencionats podem dir que esta tesi doctoral constituïx una contribució científica original al desenvolupament de la química supramolecular. Els seus resultats derivats dels estudis presentats deixen rutes obertes per a continuar l'estudi i el desenvolupament de nous materials hibrids i sensors químics més eficients per a aplicacions biomèdiques i terapeutiques.
De La Torre Paredes, C. (2017). Nanotechnology and supramolecular chemistry in controlled release and molecular recognition proceses for biomedical applications" [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/94043
TESIS

[ES] La presente tesis doctoral titulada "Sistemas de liberacio'n controlada de fa'rmacos diseñados para mejorar el tratamiento de Enfermedad Inflamatoria Intestinal" se centra en el diseño, preparación, caracterización y evaluación in vivo de distintos sistemas de liberación controlada de fármacos en colon (CDDS, por sus siglas en inglés) utilizando como soporte micropartículas de silice mesoporosa, funcionalizadas con puertas moleculares. En conclusión, los estudios realizados demuestran que los materiales de silice mesoporosa, en combinación con puertas moleculares sensibles a estímulos específicos, tienen un gran potencial para el desarrollo de nuevos sistemas de liberación controlada de fármacos en el colon, dirigidos a mejorar el arsenal terapéutico disponible para el tratamiento de EII. La posibilidad de adaptar o personalizar la carga y las puertas moleculares hace que estos soportes de sílice mesoporosa sean una opción interesante para el desarrollo de nuevos sistemas de liberación controlada de fármacos en diferentes aplicaciones biomédicas. Finalmente, esperamos que los resultados obtenidos en esta tesis doctoral sirvan de inspiración para el desarrollo de sistemas de liberación controlada de fármacos innovadores y cada vez más inteligentes, para su aplicación tanto en medicina como en otras áreas.
[CAT] La present tesi doctoral titulada "Sistemes d'alliberament controlat de farmacs dissenyats per a millorar el tractament de Malaltia Inflamatoria Intestinal" se centra en el disseny, preparacio, caracteritzacio i avaluacio in vivo de diferents sistemes d'alliberament controlat de farmacs en colon (*CDDS, per les seues sigles en angles) utilitzant com a suport microparticules de si'lice mesoporosa, funcionalitzades amb portes moleculars. En conclusio, els estudis realitzats demostren que els materials de si'lice mesoporosa, en combinacio amb portes moleculars sensibles a estimuls especifics, tenen un gran potencial per al desenvolupament de nous sistemes d'alliberament controlat de farmacs en el colon, dirigits a millorar l'arsenal terapeutic disponible per al tractament de MII. La possibilitat d'adaptar o personalitzar la carrega i les portes moleculars, fa que aquests suports de silice mesoporosa siguen una opcio interessant per al desenvolupament de nous sistemes d'alliberacio controlada de farmacs en diferents aplicacions biomediques. Finalment, esperem que els resultats obtinguts en aquesta tesi doctoral servisquen d'inspiracio per al desenvolupament de sistemes d'alliberament controlat de farmacs innovadors i cada vegada mes intel·ligents, per a la seua aplicacio tant en medicina com en altres arees.
[EN] This PhD thesis entitled "Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy" is focused on the design, synthesis, characterization and in vivo evaluation of several Colon Drug Delivery Systems (CDDS) using hybrid mesoporous silica microparticles as scaffolds containing molecular gates. In conclusion, the studies shown in this Thesis demonstrate that mesoporous silica materials in combination with responsive molecular gates have great potential in the design and preparation of new CDDS to improve the therapeutic options available for IBD. The possibility to adapt the cargo and the molecular gate makes mesoporous silica support especially appealing for similar controlled drug delivery applications in the biomedical field. We hope that the obtained results could inspire the development of new innovative smart drug delivery systems in this or other fields.
We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. We thank the Generalitat Valenciana (Project PROMETEO2018/024)
Hernández Teruel, A. (2019). Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129863
TESIS

There are several studies in order to control drug delivery, decrease the toxicity of drugs and also for novel biomedical applications. It is necessary to be able to control the release of the drug within the body by using drug delivery systems. Mesoporous silica compounds have only been discovered twenty years ago and they have already attracted many researchers to study these materials for several applications. SBA-15 particles have a highly ordered regular structure and are a good matrix for guest-host applications. The aim of this study is to be able to address whether the surface functionalization of SBA-15 samples would improve the loading of a drug into these particles. The synthesized SBA-15 particles were surface functionalized by post - grafting synthesis method in order to be used as carrier materials for drug delivery. Amoxicillin was used as a model drug. These mesoporous materials have been characterized using X-ray diffraction (XRD), small-angle X-ray spectroscopy (SAXS), fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), N2 adsorption/ desorption, solid-state silicon nuclear magnetic resonance (Si-NMR), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, elemental and thermo gravimetric analysis (TGA). The effect of concentration difference and the type of alkoxysilanes used for the functionalization have been discussed in terms of loading amoxicillin and controlling the delivery. Drug delivery systems have many further applications that still need to be investigated in areas such as neurosciences, cancer and biomedical engineering.

[ES] La presente tesis doctoral titulada "Nanodispositivos mesoporosos híbridos funcionalizados con enzimas para detección, liberación controlada y comunicación molecular" se centra en el diseño, preparación, caracterización y evaluación de distintos nanodispositivos híbridos orgánico-inorgánicos utilizando como soporte nanopartículas tipo Janus de oro y sílice mesoporosa, que se equipan con enzimas, especies fluorescentes y puertas moleculares. Como conclusión general, los estudios realizados muestran que la incorporación de enzimas sobre nanopartículas permite introducir funciones de reconocimiento con alta especificidad y diseñar nanodispositivos avanzados para distintas finalidades. La combinación de nanopartículas híbridas con grupos orgánicos como puertas moleculares, efectores enzimáticos y especies cromo- fluorogénicas o fármacos puede resultar muy versátil; y se espera que los resultados obtenidos puedan inspirar el desarrollo de nuevos materiales inteligentes con aplicación en distintas áreas como la nanomedicina y la detección de moléculas de interés.
[CAT] La present tesi doctoral titulada "Nanodispositius mesoporosos híbrids funcionalitzats amb enzims per a detecció, alliberació controlada i comunicació molecular" es centra en el disseny, preparació, caracterització i avaluació de distints nanodispositius híbrids orgànic-inorgànics utilitzant com a suport nanopartícules tipus Janus d'or i sílice mesoporosa, que s'equipen amb enzims, espècies fluorescents i portes moleculars. Com a conclusió general, els estudis realitzats mostren que la incorporació d'enzims sobre nanopartícules permeten introduir funcions de reconeixement amb alta especificitat i dissenyar nanodispositius avançats per a distintes finalitats. La combinació de nanopartícules híbrides amb grups orgànics com portes moleculars, efectors enzimàtics i espècies cromo-fluorogèniques o fàrmacs pot resultar molt versàtil; i s'espera que els resultats obsessos inspiren el desenvolupament de nous materials intel·ligents amb aplicació en distintes àrees com la nanomedicina i la detecció de molècules d'interés.
[EN] This PhD thesis entitled "Enzyme-functionalized hybrid mesoporous nanodevices for sensing, controlled release and molecular communication" is focused on the design, synthesis, characterization and evaluation of several hybrid organic-inorganic nanodevices using Janus gold-mesoporous silica nanoparticles as scaffolds, equipped with enzymes, fluorescent species and molecular gates. In conclusion, these studies show that the incorporation of enzymes on nanoparticles allows to introduce recognition capabilities with high specificity and to design advanced nanodevices for different purposes. The combination of hybrid nanoparticles with organic groups such as molecular gates, enzymatic effectors and chromo-fluorogenic species or drugs can be very versatile; and we hope that the obtained results inspire the development of new smart materials with application in different areas such as nanomedice and sensing.
Llopis Lorente, A. (2019). Enzyme-functionalized hybrid mesoporous nanodevices for sensing, controlled release and molecular communication [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/117612
TESIS

In this thesis, the incorporation of drug loaded mesoporous magnesium carbonate as an excipient for the additive manufacturing of oral tablets by fused deposition modeling was investigated. Cinnarizine, a BCS class II drug, was loaded into the pores of the mesoporous material via a soaking method, corresponding to a drug loading of 8.68 wt%. DSC measurements on the loaded material suggested that the drug was partially crystallized after incorporation, meanwhile the XRD diffractogram implied that the drug was in a state lacking long range order. The drug loaded material was combined with two pharmaceutical polymers, Aquasolve LG and Klucel ELF, and extruded into filaments with a single screw extruder. Filaments of Klucel ELF and drug loaded Upsalite (30:70 wt% ratio) were successfully implemented for the printing oral tablets, in contrast to the Aquasolve LG based filaments which were difficult to print due to thickness variations and non-uniform material distributions. The drug content obtained by TGA suggested drug loadings of 7.71 wt% and 2.23 wt% in the drug loaded Upsalite and tablets respectively. Dissolution studies using an USP II apparatus showed a slower API-release from the tablets in comparison to the crystalline drug, most probably due to slow diffusion of drug species through the polymeric matrix. For future studies, pharmaceutical polymers with higher aqueous solubility should be investigated in order to thoroughly examine the potential of utilizing the immediate release property of Upsalite.

Mesoporous zirconia nanoparticles (MZN) are a promising inorganic drug-delivery system (DDSs). The design and development regarding MZNs with stimuli-responsive (pH-dependent) drug-releasing capability, aims at enhancing the efficiency and minimizing the side effects of antimicrobial drugs for bacterial infections. In this thesis, special attention is paid to the functionalization of MZNs as carriers in DDSs. Zirconia is a biocompatible material that possesses good chemical inertness, mechanical and thermal properties. Highly efficient, neutral-surfactant assisted sol-gel method is used for the synthesis of spherical MZNs with the high surface area makes it suitable for drug delivery. Scanning electron microscopy, X-ray diffraction, BET isotherm, size plot distribution, loading, and release of trapped drug test has been done. Daptomycin is an anti bactericidal drug that degrades the protein synthesis takes place in Gram-positive staphylococcus aureus, the most problematic one worldwide. Drug loading is achieved by a simple impregnation process at acidic pH. a basic pH offers a faster DPT release from MZN, such property makes the loaded DPT release easily from the nanoparticles to the targeted-site with good efficiency. All the bacterial test results are discussed below in the thesis.

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Superhydrophobicity is a property of material surfaces reflecting the ability to maintain air at the solid-liquid interface when in contact with water. These surfaces have characteristically high apparent contact angles, by definition exceeding 150°, as a result of the composite material-air surface formed under an applied water droplet. Superhydrophobic surfaces were first discovered on naturally occurring substrates, and have subsequently been fabricated in the last several decades to harness these favorable surface properties for a number of emerging applications, including their use in biomedical settings. This work describes fabrication and characterization of superhydrophobic 3D materials, as well as their use as drug delivery devices. Superhydrophobic 3D materials are distinct from 2D superhydrophobic surfaces in that air is maintained not just at the surface of the material, but also within the bulk. When the superhydrophobic 3D materials are submerged in water, water infiltrates slowly and continuously as a new water-air-material interface 1s fonned with controlled displacement of air. Electrospinning and electrospraying are used to fabricate superhydrophobic 3D materials utilizing blends of the biocompatible polymers poly(ε-caprolactone) and poly(caprolactone-co-glycerol monostearate) (PGC-C18). PGC-C18 is significantly more hydrophobic than PCL (contact angle of 116° versus 83° for flat materials), and further additions of PGC-C18 into electrospun meshes and electrosprayed coatings affords increased stability of the entrapped air layer. For example, PCL meshes alone (500 µm thick) take 10 days to fully wet, and with 10% or 30% PGC-C18 addition wetting rates are dramatically slowed to 60% wetted by 77 days and 4% by 75 days, respectively. Stability of the superhydrophobic materials can be further probed with a variety of physio-chemical techniques, including pressure, surfactant containing solutions, and solvents of varying surface tension. Superhydrophobicity is shown to be enhanced with further increases in PGC-C18 content and surface roughness (a decrease in fiber size). We demonstrate the utility of superhydrophobicity as a method for drug delivery. When the camptothecin derivatives SN-38 and CPT-11 are encapsulated within electrospun meshes, changes in air layer stability (due to changes in PGC-C 18 content) dictate the rate of drug release by controlling the rate in which water can permeate into the porous 3D electrospun structure. Drug release can be tuned from 2 weeks to > 10 weeks from 300 µm meshes, and meshes effectively kill a variety of cancer cell lines (lung, colon, breast) when utilized in a cytotoxicity assay. After determining that air could be used to control the rate of drug release, superhydrophobic 3D materials are explored for three applications. First, meshes are considered as a potential combination reinforcement-drug delivery device for use in resectable colorectal cancer. Second, removal of the air layer in superhydrophobic meshes is used as a method to trigger drug release. The pressure generated from high-intensity focused ultrasound (0.75-4.25 MPa) can remove the air layer spatially and temporally, allowing drug release to be controlled with application of a sufficient treatment. Third, "connective" electrosprayed coatings are deposited on chemically distinct material surfaces, which are both three-dimensional and mechanically robust. In summary, superhydrophobic 3D materials are fabricated and characterized, and are utilized as drug delivery devices. Controlled air removal from these materials offers an entirely new strategy for drug delivery, and is promising for the applications considered in this work as well as many others.

En la present tesi doctoral, s'ha desenvolupat un sistema d'alliberament de fàrmacs sensible a pH basat en nanopartícules mesoporoses de sílice (MSN). Els porus de la nanopartícula estan radialment obstruïts mitjançant la funcionalització de cadenes de PEG, substituïdes amb un fàrmac en un dels seus extrems. L'objectiu d'aquesta nova metodologia és la de preservar la càrrega interna d'aquestes MSN. En primer lloc, s'ha estudiat el concepte d'obstrucció radial per avaluar la utilitat pràctica d'aquest mètode. Per aquesta raó, diferents tipus de cadenes de PEG amb càrrega, a saber, amines quaternàries i PEG neutrals, s'han funcionalitzat sobre la MSN per estudiar la seva capacitat d'obstrucció. Com a prova de concepte, s'ha estudiat l'alliberament de safranina en medi fisiològic (pH 7.4). Els resultats obtinguts han demostrat que les cadenes de PEG que contenen una càrrega positiva obstrueixen millor els porus que les cadenes de PEG neutres de la mateixa longitud. Utilitzant aquesta aproximació, s'ha dissenyat un sistema d'alliberament de fàrmacs per a la vehiculització de camptotecina (CPT) i topotecan (TPT). En primer lloc, un dels anteriors fàrmacs s’ha adsorbit dins dels porus de la MSN. Posteriorment, els porus s’han segellat mitjançant una cadena de PEG que conté doxorrubicina (DOX) en un dels seus extrems (DOX-PEG). L'estabilitat d'aquest sistema en condicions fisiològiques prova l'eficàcia de l'obstrucció radial. D'altra banda, en condicions àcides, es produeix un alliberament descontrolat dels fàrmacs. Així mateix, els experiments de citotoxicitat in vitro han demostrat que el sistema pot alliberar CPT i DOX en les cèl·lules cancerígenes HeLa, aconseguint un major efecte sinèrgic que la combinació de TPT i DOX. També s'ha sintetitzat un profàrmac de la CPT amb l'objectiu d'augmentar la seva càrrega en una MSN i millorar així el seu efecte sinèrgic amb la DOX. Per dur-ho a terme, s’ha unit una cadena de PEG escindible a la CPT. Emprant aquesta estratègia s'ha aconseguit carregar un 30% més de CPT a l'interior de les MSN. El sistema mostra una gran estabilitat en condicions fisiològiques, ja que s’observa un alliberament negligible dels fàrmacs. A més, s'ha avaluat la citotoxicitat de sistema en dues línies cel·lulars diferents: HeLa i HepG2. Els resultats obtinguts demostren que el nou profàrmac sintetitzat amb combinació amb la DOX té un major efecte sinèrgic en les cèl·lules HepG2. D'altra banda, la selectivitat de les MSN cap a les cèl·lules HepG2 s'ha millorat mitjançant la funcionalització sobre el grup DOX-PEG amb el lligant àcid glicirretinic (GA). Per fer-ho, s'ha emprat la mateixa aproximació radial establerta pels altres sistemes. Els estudis d'internalització cel·lular han demostrat que aquest nou sistema és capaç de discriminar entre cèl·lules HeLa i HepG2, acumulant-se preferentment en aquestes últimes. Finalment, s'ha avaluat un sistema d'administració triple de medicaments amb l'objectiu de superar l'efecte de resistència dels tumors a múltiples fàrmacs. Aquesta acció es pot emprendre mitjançant la combinació d’agents quimioterapèutics, DOX i CPT, amb un agent fototerapèutic (ftalocianina). Referent a això, s'ha sintetitzat un nou conjugat de la CPT amb una ftalocianina. Aquest conjugat s'ha carregat dins dels porus de la MSN i posteriorment s'han segellat amb el grup DOX-PEG. Els experiments d'internalització cel·lular han demostrat l'endocitosi d'aquest sistema en les cèl·lules HeLa i el posterior alliberament dels fàrmacs. Així mateix, s'ha avaluat in vitro l'efecte sinèrgic entre la DOX i la CPT.
En la presente tesis doctoral, se ha desarrollado un sistema de liberación de fármacos sensible a pH basado en nanopartículas mesoporosas de sílice (MSN). Los poros de la nanopartícula están radialmente obstruidos mediante la funcionalización de cadenas de PEG, sustituidas con un fármaco en uno de sus extremos. El objetivo de esta nueva metodología es la de preservar la carga interna de estas MSN. En primer lugar, se ha estudiado el concepto de obstrucción radial para evaluar la utilidad práctica de este método. Por esta razón, diferentes tipos de cadenas de PEG con carga, a saber, aminas cuaternarias y PEG neutrales, se han funcionalizado sobre la MSN para estudiar su capacidad de obstrucción. Como prueba de concepto, se ha estudiado la liberación de safranina en medio fisiológico (pH 7.4). Los resultados obtenidos han demostrado que las cadenas de PEG que contienen una carga positiva obstruyen mejor los poros que las cadenas de PEG neutrales de la misma longitud. Utilizando esta aproximación, se ha diseñado un sistema de liberación de fármacos para la vehiculización de camptotecina (CPT) y topotecán (TPT). En primer lugar, uno de los anteriores fármacos se ha adsorbido dentro de los poros de la MSN. Posteriormente, los poros se han sellado mediante una cadena de PEG que contiene doxorrubicina (DOX) en uno de sus extremos (DOX-PEG). La estabilidad de dicho sistema en condiciones fisiológicas prueba la eficacia de la obstrucción radial. Por otro lado, en condiciones ácidas, se produce una liberación descontrolada de los fármacos. Asimismo, los experimentos de citotoxicidad in vitro han demostrado que el sistema puede liberar CPT y DOX en las células cancerígenas HeLa, logrando un mayor efecto sinérgico que la combinación de TPT y DOX. También se ha sintetizado un profármaco de la CPT con el objetivo de aumentar su carga en una MSN y mejorar así su efecto sinérgico con la DOX. Para llevarlo a cabo, se ha unido una cadena escindible de PEG a la CPT. Empleando esta estrategia se ha conseguido cargar un 30% más de CPT en el interior de las MSN. El sistema muestra una gran estabilidad en condiciones fisiológicas, ya que se observa una liberación negligible de los fármacos. Además, se ha evaluado la citotoxicidad del sistema en dos líneas celulares diferentes: HeLa y HepG2. Los resultados obtenidos demuestran que el nuevo profármaco sintetizado en combinación con DOX, resulta en un mayor efecto sinérgico en las células HepG2. Por otro lado, la selectividad de las MSN hacia las células HepG2 se ha mejorado mediante la introducción del ligando ácido glicirretínico (GA) sobre el grupo DOX-PEG. Para llevarlo a cabo, se ha empleado la misma aproximación radial establecida para los otros sistemas. Los estudios de internalización celular han demostrado que este nuevo sistema es capaz de discriminar entre las células HeLa y HepG2, acumulándose preferentemente en estas últimas. Finalmente, se ha evaluado un sistema de administración triple de medicamentos con el objetivo de superar el efecto de resistencia de los tumores a múltiples fármacos. Esta acción se puede emprender mediante la combinación de medicamentos quimioterapéuticos, DOX y CPT, con un agente fototerapéutico (ftalocianina). Por esta razón, se ha sintetizado un nuevo conjugado de la CPT con una ftalocianina. Dicho conjugado se ha cargado dentro de los poros de la MSN y posteriormente se han sellado con el grupo DOX-PEG. Los experimentos de internalización celular han demostrado la endocitosis de este sistema en las células HeLa y la posterior liberación de los fármacos. Asimismo, se ha evaluado in vitro el efecto sinérgico entre la DOX y la CPT.
In this PhD dissertation, a pH-responsive multiple drug delivery system (DDS) based on mesoporous silica nanoparticles (MSN) with a radial-capping of its pores has been developed. This is a new concept that relies on the functionalization of the particle surface with PEG chains substituted with a drug at its end to preserve the inner cargo of the MSN. First, the concept of radial-capping has been studied to assess the practical usefulness of such capping method. Thus, different types of charged PEGs, namely quaternary amines and neutral PEGs, have been introduced upon an MSN in order to study its capping ability. As a proof of concept, the dye safranin was loaded into the nanoparticles pores, which were subsequently capped with PEGs chains. Then, the release of safranin was assessed under physiological conditions (pH 7.4). The results obtained demonstrated that PEG chains possessing positive charge provides a more efficient capping than the neutral PEGs of the same length. Using this approach, a drug delivery system (DDS) based on the radial capping for the delivery of camptothecin (CPT) and topotecan (TPT) has been studied. CPT or TPT has been loaded within the pores of an MSN, and subsequently sealed with a PEG chain decorated with doxorubicin (DOX) at its end (DOX-PEG moiety). The system is stable under physiological conditions (pH 7.4) which confirms the effectiveness of the radial capping. On the other hand, under acidic pH, a burst release of drugs takes place. Furthermore, the in vitro cytotoxicity test has demonstrated that this DDS can effectively deliver CPT and DOX to HeLa cells achieving a better synergistic effect than the combination of TPT and DOX. With the aim to improve the loading of CPT to enhance the synergistic effect with the latter system (DOX-PEG moiety), a prodrug of CPT has been synthesised. To do so, a cleavable reductive short PEG chain has been bonded to CPT. An increase of loading of 30% has been achieved in comparison with the unmodified drug. The stability of the radial-capping methodology has been tested as mentioned above. Under physiological conditions, the release of drugs is negligible. The cytotoxicity activity of the system has been tested in two different cell lines: HeLa and HepG2 cells. The results showed a better synergistic effect of this new synthesised system towards HepG2 cells. In order to further improve the selectivity of the system towards HepG2 cells, the MSN were decorated with glycyrrhetinic acid (GA) ligand over the DOX-PEG moiety. Uptake studies have shown that this new system preferably accumulates in HepG2 cells in comparison to HeLa cells. Finally, a tri-deliver system of drugs has been developed with the aim to try to overcome the multiple drug-resistant (MDR) effect by the combination of chemotherapeutic drugs (DOX and CPT) with a phototherapeutic agent (phthalocyanine). In this regard, a new CPT conjugate with a phthalocyanine has been synthesised and loaded within the pores of an MSN. Then, the system has been sealed with the DOX-PEG moiety. The uptake studies have demonstrated the proper endocytosis of the system inside HeLa cells and the subsequent delivery of the three drugs in the cytoplasm and nucleus. Furthermore, the synergistic effect of DOX and CPT has been assessed in vitro.

Zeolites and mesoporous silica were used as drug delivery systems for the loading and release of small drug molecules, aspirin and 5-fluorouracil. Different parameters were varied such as aluminum content in the zeolite, effect of distribution of functional groups and the method of surface modification in case of mesoporous silica. The effect of the aforementioned variables was studied on drug loading and release from these microporous and mesoporous systems. The drug loaded materials were extensively characterized using various physical techniques such as powder X-ray diffraction, nitrogen isotherms, infrared spectroscopy, solid state NMR and thermogravimetric analysis. Quantum calculations and molecular dynamics simulations were performed in order to validate the experimental data and also to obtain a molecular level insight of the drugs inside the pores of the host materials. Drug templated synthesis of mesoporous silica was also carried out in the presence of aspirin as the template. The aspirin templated material was characterized by aforementioned techniques and showed a sustained drug release profile.

Porous silicon (Psi) and nanocellulose (NC) hydrogels are nanostructured materials with several properties that make them promising for drug delivery applications. In this work, β-carotene (BC) and clofazimine (CFZ) are used as model molecules to investigate the physical and chemical processes governing the interactions of hydrophobic molecules with both inorganic (Psi) and organic (NC) nanostructured carriers. Despite the large number of advantages, Psi does not perform well as carrier for BC, since it stimulates the molecule degradation even if its surface is carefully passivated. Furthermore, during the release experiments, BC tends to nucleate on Psi surface forming aggregates whose dissolution is much slower than the BC molecules release, thus they negatively impact on the control over the drug release. On the other hand NC hydrogels do not pose heavy issues to the release of lipophilic drugs, provided that a suitable surfactant (either Tween-20 or Tween-80) mediates the molecule solvation and its subsequent release into aqueous media. Moreover, NC gels protect BC from degradation much better than its storage in freezer or in organic solvent, making these carriers interesting for DD.

Porous silicon (Psi) and nanocellulose (NC) hydrogels are nanostructured materials with several properties that make them promising for drug delivery applications. In this work, β-carotene (BC) and clofazimine (CFZ) are used as model molecules to investigate the physical and chemical processes governing the interactions of hydrophobic molecules with both inorganic (Psi) and organic (NC) nanostructured carriers. Despite the large number of advantages, Psi does not perform well as carrier for BC, since it stimulates the molecule degradation even if its surface is carefully passivated. Furthermore, during the release experiments, BC tends to nucleate on Psi surface forming aggregates whose dissolution is much slower than the BC molecules release, thus they negatively impact on the control over the drug release. On the other hand NC hydrogels do not pose heavy issues to the release of lipophilic drugs, provided that a suitable surfactant (either Tween-20 or Tween-80) mediates the molecule solvation and its subsequent release into aqueous media. Moreover, NC gels protect BC from degradation much better than its storage in freezer or in organic solvent, making these carriers interesting for DD.

Ordered mesoporous materials (OMMs) are characterized by high surface area (up to 1000 m2/g), high pore volume (1-3 cm3/g) and narrow pore size (2-30 nm) distribution. Recently, mesoporous silica nanoparticles (MSNs), a subclass of OMMs, have had great development as nanocarriers for drug delivery, particularly for cancer treatment. The research activity of my PhD work was aimed to study SBA-15 and MCM-41 mesoporous silica samples for biomedical applications. The texture and the structure of the synthesized materials were characterized through N2 adsorption/desorption isotherms, SAXS, and TEM. The functionalization of the mesoporous silica samples was verified by means of Fourier-transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). DLS and ELS were used to determinate hydrodynamic diameter and zeta potential of the studied systems under different conditions. The PhD thesis focused on different aspects of the use of OMMs, particularly MSNs, as drug nanocarriers. In the first paper how different features of OMMs (surface area, pore size and surface charge) can affect the adsorption and release of drugs was investigated. Ampicillin, a penicillin-like -lactam antibiotic was loaded on MCM-41, SBA-15, and amino-functionalized SBA-15, then its release in simulated physiological conditions was studied. This study demonstrated that to obtain a sustained drug release, the chemical nature of the matrix’s surface plays a role which is more important than its textural features. SBA-15-NH2 matrix is a suitable candidate as depot system for local sustained release of ampicillin. Common target systems have the disadvantage that the targeting molecule can be recognized by several receptors. A possible strategy to solve this issue was investigated in the second paper. The targeting molecule was hidden by preparing a double sequential targeting system. To this purpose a double target system was synthesized. Alendronate was used as a tissue target to recognize a diseased bone, and an encrypted cellular target, Arg-Gly-Asp (RGD) was used to improve the internalization in human osteosarcoma cells (collaboration with Universidad Complutense de Madrid). This preliminary study showed the efficacy of the double target systems. The next step could be the functionalization of MSNs with the previously described systems for the synthesis of a smart target systems usable as a carrier for anticancer drugs against bone cancer. In the third paper, the effect of surface charge on the internalization of MCM-41-type MSNs, functionalized with chitosan (CHIT) and hyaluronic acid (HA) biopolymers, on 3T3 mouse fibroblast cells was then investigated. The opposite surface charge of the biopolymer-functionalized MSNs (negative for MSN-HA and positive for MSN-CHIT) gave a different interaction with BSA, used as a model protein to investigate the formation of the protein corona (forth paper). Finally, in the fifth paper, MSNs were functionalized with HA samples having three different molecular weights (HAS, HAM, and HAL). The effect of HA molecular weight on the internalization of HA-MSNs particles on HeLa cells was evaluated. These last studies showed the importance of the external functionalization on the interaction between MSNs and the components of body fluids, that change their surface properties. These changes as well as the polymer’s features (i.e. the molecular weight) are able to modulate the cellular uptake. The obtained results highlight the importance of the physico-chemical phenomena occurring at the nano-biointerface for the future use of functionalized OMMs and MSNs in nanomedicine. The present findings confirm that these nanocarriers are very promising matrices for the obtainment of targeting drug delivery systems for cancer treatment.

Proliferative vitreoretinopathy, a potentially blinding condition, involves excessive proliferation of retinal pigment epithelium (RPE) cells and is the main complication following retinal detachment (RD). Complicated cases of RD are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. The aim of this study was to investigate different methodologies to develop a sustained and controlled drug release of anti-proliferative and anti inflammatory drugs from SiO tamponades using all-trans retinoic acid (atRA) and ibuprofen (Ibu). In detailed studies of atRA and Ibu, including atRA degradation behaviour, the drugs were found to be non-toxic to an adult RPE cell line (ARPE 19) below 10-5 M. The solubility of both drugs in SiO was assessed using radioisotope techniques. Prodrugs of atRA and Ibu were synthesised via conjugation to polyethylene oxide (PEO), and cleavage of the resulting ester bond, toxicity towards RPE cells, solubility in SiO and release into media were assessed. Prodrug cleavage was successful in vitro for Ibu but not achieved in the case of atRA due to its highly conjugated nature. Cytotoxicity assays showed PEO attachment had no effect on cytotoxicity and PEO prodrug solubility in SiO followed the expected trend of decreasing solubility with increased PEO chain length. Overall the saturation concentration of drug in SiO achieved through the use of PEO-prodrugs was too low for an effective therapy. Lipophilic prodrugs with a poly(dimethylsiloxane) (PDMS) pro-moiety were synthesised and investigated. Their cleavage was problematic due to PDMS being highly hydrophobic and cleavage could only be achieved in vitro when a small hydrophilic spacer was added between PDMS and the drug. The effects of PDMS prodrugs as additives in SiO were investigated and the presence of PDMS-atRA in SiO was shown to have a positive effect on both atRA solubility and longevity of release. The clinically-relevant release period (6-8 weeks) was independent of atRA starting concentration but dependant on the PDMS-atRA concentration within the blend. This has potential for further development into tamponade drug reservoirs for future patient benefits. A series of linear and branched amphiphilic copolymer architectures were also evaluated as additives for SiO. Monomer selection included oligoethylene oxide methacrylate (OEGMA), 2-hydroxyethyl methacrylate, PDMS-methacrylate (PDMSMA) and the brancher PDMS-dimethacrylate (PDMSDMA). SiO solubility of p(OEGMA-co-PDMSDMA) was investigated and copolymers which contained the smallest hydrophilic and largest lipophilic components only achieved small solubility (0.1 % v/v). To overcome these solubility issues, hydrophobic PDMSMA monomer was utilised. Both linear p(PDMSMA-co-OEGMA) and branched p(PDMSMA-co-OEGMA-co-PDMSDMA) were successfully synthesised and displayed high solubility within SiO, up to 40-50 % v/v. The potential for SiO tamponades as long-acting drug reservoirs has been demonstrated after inclusion of a novel end-modified PDMS additive leading to long term release of atRA. The formation of novel polymer architectures that show considerable miscibility with SiO also shows the scope of the opportunity for further additive development to tailor release profiles.

Drug delivery systems (DDS) with multiple functionalities such as environment-sensitive drug release mechanisms and visualization agents have motivated the biomedical community as well as materials chemists for more than a decade. This dissertation is concerned with the development of nanoparticles for multifunctional DDS  to tackle several crucial challenges in these complex systems, including polymeric nanospheres which respond to temperature change, superparamagnetic iron oxide nanoparticles/polymeric composite for magnetic resonance imaging contrast agents and drug carriers, immunoresponse of nanomaterials and injectable magnetic field sensitive ferrogels. The biocompatible and biodegradable polylactide (PLA) was employed as matrix materials for polymeric nanosphere-based DDS. The thermosensitive polymeric nanospheres have been constructed through a “modified double-emulsion method”. The inner shell containing the thermosensitive poly(N-isopropylacrylamide) (PNIPAAm) undergoes a “hydrophilic-to-hydrophobic” phase transition around the human body temperature. The sensitivity of the polymer to the temperature can facilitate drug release at an elevated temperature upon administration. In addition, gold nanoparticles were assembled on the dual-shell structure to form a layer of gold shell. The cell viability was found to be enhanced due to the gold layer. The immunoresponse of the gold nanoparticles has been considered even if no acute cytotoxicity was observed. Imaging is another functionality of multifunctional DDS. This work focuses on magnetic resonance imaging (MRI) and involves synthesis and surface modification of superparamagnetic iron oxide nanoparticles (SPIONs) for contrast agents. The SPIONs have been prepared through a high temperature decomposition method. Surface modification was carried out in different ways. Poly(L,L-lactide) (PLLA) was grafted on SPIONs through surface-initiated ring-opening polymerization. The hydrophobic model drug indomethacin was loaded in the PLLA layer of the composite particles. For biomedical applications, it is essential to modify the hydrophobic particles so that they can be dispersed in physiological solutions. A series of protocols including using small charged molecules and amphiphilic polymers has been established. Pluronic F127 (PF127), a triblock copolymer was applied as a phase transfer reagent. Most interestingly, PF127@SPIONs show remarkable efficacy as T2 contrast agents. The PF127@SPIONs have been successfully applied to image the cochlea in a rat model. As another phase transfer reagent, poly(maleic anhydride-alt-octadecene)-graft-PNIPAAm (PMAO-graft-PNIPAAm) was created for surface modification of SPIONs. This new copolymer provides the modified SPIONs with thermosensitivity together with water-dispersibility. As another form of DDS, ferrogel made of PF127 copolymer and SPIONs was developed. Gelation process depends on the temperature of the SPIONs/PF127 mixture. This property makes it possible to use the ferrogel as an injectable drug carrier. Unlike other ferrogels based on crosslinked polymeric network, the PF127 ferrogel can entrap and release hydrophobic drugs. Application of an external magnetic field is found to enhance the drug release rate. This property can find application in externally stimulated local drug release applications.
QC20100722

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007.
"May 2007." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 19).
There is considerable amount of interest in the immediate treatment of personnel involved in high risk situations on the battlefield. A novel approach to drug delivery on the battlefield based on MEMS technology is discussed. By combining three separately fabricated layers, a single implantable drug delivery device capable of delivering up to 100 mm3 of a vasopressin solution was developed. In vitro release of vasopressin was observed and the I-V response of the bubble generator was characterized. Results show that the voltage at the time of release is ~11V while the current is ~0.35A, giving a power output of 3.79W. The time to total release of the drug was less than 2 minutes.
by Wang Lei.
S.B.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005.
Includes bibliographical references (p. 52-55).
Local drug delivery is a fast expanding field, and has been a center of attention for researchers in medicine in the last decade. Its advantages over systemic drug delivery are clear in cancer therapy, with localized tumors. A silicon microelectromechanical drug delivery device was fabricated for the purpose of delivering chemotherapeutic agents such-as carmustine, a potent brain cancer drug, directly to the site of the tumor. Limitations in the delivery capacity of the device led to the design of a new package. This package is made from thermally bonded Pyrex® 7740 frames that are anodically bonded to the drug delivery chip. It increases the capacity of the chip, is smaller than the previous package and possesses true hermeticity, because of the bonding processes involved. This work describes the fabrication steps of the new package and a problem with the thermal bonding of Pyrex® frames preventing the achievement of a package true to the original design. A temporary solution was devised and the completed package was tested with regards to its intended goals. It managed to increase the load capacity of the chip by a, factor of 10, with potential for more, while decreasing the overall size of the package. Short-term hermeticity was achieved for this package by using a UV-cured epoxy to bond some pieces, which was not in the original design. Future work will focus on finding a permanent solution to the aforementioned problem, and directions for it were suggested.
by Hong Linh Ho Duc.
S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2009.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student submitted PDF version of thesis.
Includes bibliographical references.
An implantable rapid drug delivery device based on micro-electro-mechanical systems (MEMS) technology was designed, fabricated and validated for the in vivo rapid delivery of vasopressin in a rabbit model. In vitro characterization of device performance found the device capable of reliably and reproducibly delivering 85% of its loaded drug solution. A comparison of intraperitoneal and subcutaneous injections of vasopressin in rabbits was performed to determine the implantation location for the device. Both routes of delivery were found to be viable implantation locations, and the less invasive subcutaneous site was chosen. Vasopressin was released from the subcutaneously implanted device in anesthetized rabbits and found to exert a measurable effect on blood pressure. The bioavailability of vasopressin delivered from the device was found to be 6.2% after one hour. Proof-of-concept experiments were also conducted to address long-term stability of drugs in the implanted device and wireless activation of the device. These experiments defined areas of future research for improvement of the device.
by Hong Linh Ho Duc.
Ph.D.

The main objective of this work was to develop a novel drug delivery system exploiting special opportunities afforded by synthesis of nanoscale materials to be applied inside the colon. It must be robust enough to cope with the adverse conditions in the gastrointestinal tract (GI) and be able to reach and release “on demand” at the colon area at the right time. In this work, an oral capsule formulation with iron oxide nanoparticles (IONs) containing coating was used to transport drug and release drug in the colon. With that in mind, the synthesis of poly (alkylcyanoacrylate) nanocapsules by microemulsion polymerisation and magnetic iron oxide nanoparticles (IONs) via a coprecipitation method were conducted. The key physical properties of the materials were characterized employing standard techniques such as HPLC, FTIR, DSC, DLS, XRD, TEM and SEM. Hard capsules filled with model drug, paracetamol, were coated with IONs containing coatings (fatty acids and paraffin). The optimum composition for the formulation of the coating embedded with the nanoparticles was explored with respect to protection of the drug payload from conditions in the GI tract as well as for effective release “on demand” using radio-frequency hyperthermia. The optimum radiofrequency and the power level for heating the nanoparticles were also determined and melting the coating using magnetic nanoparticle hyperthermia. Results showed that paraffin-based coatings had appropriate properties for this application. Finally, taking into account all the results, a design of a novel drug delivery system, together with an experimental setup for testing the “release in demand” was proposed. The approach is generic, easy to set up and could also be applied to many other situations where delivery on demand is required.

Mesoporous silica particles are of significant interest for biomedical applications due to their good general biocompatibility compared to other nanoparticle matrices such as quantum dots, high specific surface areas up to 1000 m2/g, and extreme synthetic tunability in terms of particle size, pore size and topology, core material, and surface functionalization. For one application, drug delivery, mesoporous silica nanoparticles (MSNs) of two pore structures, MCM-41 – parallel, hexagonally ordered pores approximately 3 nm in diameter – and wormhole (WO) – interconnected, disordered pores also approximately 3 nm in diameter – were synthesized with particle diameters under 100 nm. Additionally, a magnetic Fe3O4 nanoparticle core was incorporated into Fe3O4-core WO-MS-shell particles. The particles were loaded with doxorubicin, a chemotherapeutic, and the drug release into phosphate buffered saline (PBS, 10 mM, pH 7.4) at 37 °C was monitored by fluorescence spectroscopy. The data were fit to three models: Korsmeyer-Peppas, first order exponential release, and Weibull. The Korsmeyer-Peppas model provided useful information concerning the kinetics and mechanism of drug release from each MSN type. A small but statistically significant difference in the release kinetics was found due to the different pore topologies. A much larger kinetic effect was observed due to the inclusion of an iron oxide core. Applying a static magnetic field to the Fe3O4-core WO-MS shell particles did not have a significant impact on the doxorubicin release. This is the first time that the effects of pore topology and iron oxide core have been isolated from pore diameter and particle size for these materials. In vitro cell studies were conducted to determine the cytotoxicity of the bare and doxorubicin-loaded materials against three cancerous cell lines – A549 human lung carcinoma cells, HEC50CO human endometrial cancer cells, and CT26 mouse colon cancer cells. The MCM-41 and WO MSNs generally displayed similar toxicities within each cell line, and the Fe3O4-core WO-MS shell particles were less toxic. Doxorubicin-loaded particles generally displayed greater toxicity than bare MSNs, but the A549 cells were very resistant to all concentrations of MSNs tested. For another biomedical application, tissue phantom development, mesoporous silica particles with approximately 10 μm diameters and C18 surface functionalization were evaluated for their use as a substrate for optical tissue phantoms. Tissue phantoms are synthetic imitations of biological material, and C18-modified silica provides a substrate that is simple to load with optically active biological molecules. The molecules are then hydrophobically trapped to maintain a clear optical boundary between the biological loading within the particle and an aqueous suspension gel. Several preparation techniques were evaluated for the dispersal of hydrophobic particles in aqueous media, and qualitative analysis indicated that surfactant coating of the outer surface could fully disperse the hydrophobic particle while maintaining the clear optical boundary. A novel analysis was developed to provide a single numerical indicator of clustering for a quantitative assessment of particle dispersal in tissue phantoms.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2010.
Includes bibliographical references (p. 87-93).
Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Localized delivery of potent chemotherapeutics aims to lower systemic toxicity while increasing drug concentrations directly to the tumor site. I have developed implantable drug delivery microcapsule devices for the localized delivery of temozolomide and for treatment of glioblastoma multiforme in this work. I have been able to modulate the drug release profiles from these microcapsules based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. Experimental in vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The experimental release curves showed mass flow rates of 36 ug/hr for single-orifice devices and an 88 ug/hr mass flow rate for multiple-orifice devices loaded with temozolomide. Intracranial temozolomide-filled microcapsules were tested in a rodent 9L glioma model. Outcomes were animal survival and immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results showed that localized delivery of chemotherapeutics from microcapsule devices is capable of prolonging animal survival and may offer an alternative to the harsh side-effects and low response rates inherent to systemic drug administration in GBM patients.
by Alexander Wesley Scott.
S.M.

The aim of this project was to develop injectable materials to repair damaged bone and, to simultaneously release antibacterial drugs and genes in a controllable manner. Fluid poly (propylene glycol -co- lactide) dimethacrylate (PGLA-DMA) was first synthesised and then filled with varying levels of β- tricalcium phosphate (β-TCP) and monocalcium phosphate monohydrate (MCPM) to fabricate composite materials. For all formulations (including polymer and composites), full methacrylate conversion was found to occur within 200 s of exposure to blue light. The initial dry polymer modulus was enhanced three-fold by increasing total filler content to 70%. After composite immersion in water, β-TCP and MCPM was found to react and re-precipitate within the set materials as dicalcium phosphate (DCP, i.e. brushite and monetite). At higher MCPM levels there was an increase in DCP formation, composite degradation rate, release of both calcium and phosphate ions and buffering of acidic polymer degradation products. Additionally, bone-like MG-63 cells were found to attach, spread and proliferate on both the polymer and the composite surfaces and, composites implanted into chick embryo femurs demonstrated close apposition to the host tissue. To examine the potential value for drug delivery, both the polymer and the composites were prepared containing 10% of the antibacterial chlorhexidine (CHX). The drug was found to be released from material via diffusion, which increased along with antibacterial activity when the filler content was raised. PGLA-DMA polymer was additionally prepared containing complexes of the commercial cationic lipid MetafecteneTM Pro and green fluorescent protein plasmid DNA. Initial studies demonstrated that the components released from the materials were capable of gene transfection into human bone-forming mesenchymal stem cells in vitro. These studies thus demonstrate that the injectable, rapidly settable PGLADMA materials produced here might have clinical potential as both bone adhesives and drug delivery devices.

Mesoporous silica particles offer great potential benefits as vehicles for drug delivery and in other biomedical applications. They present a high loading capacity due their ordered and size-tuneable pores that allow molecules to be loaded and released. In addition, they offer the possibility to enhance oral bioavailability of drugs with limited aqueous solubility and to protect pH sensitive drugs from the acidic conditions in the stomach on their way to the intestine. The aim of this thesis was to evaluate the biocompatibility and effects of mesoporous silica particles on immunocompetent cells. Subsequently, two potential life sciences applications were investigated: as adjuvants and as weight reduction agents. Adjuvants are used in vaccines in order to enhance the immunological response towards attenuated and poorly immunogenic antigens. Their function can be mediated through dendritic cells which have a central role in the control of adaptive immunity including immunological memory. Our results show that different types of mesoporous silica particles were able to tune the development of T cells both in human cell cultures and in mice. In contrast to the approved adjuvant alum (aluminium salts) which is a specific inducer of Th2-type immune responses, the particles induced more Th1-like responses, which may be desired in vaccines against allergy and intracellular pathogens such as viruses. Particle exposure to macrophages did not affect their cell function which is crucial for tissue homeostasis, wound repair and in prevention of autoimmune responses. Likewise, the cytokine secretion was not affected, which suggest that macrophages would not modulate the immune response towards the particles. Furthermore, mesoporous silica particles were highly tolerated at daily oral administrations of up to 2000 mg/kg doses for some of the materials prepared. Large pore mesoporous silica particles were shown to act as weight and body fat reduction agents without other observable pathological signs when administered in the diet of obese mice. Together; those results are promising for the development of mesoporous silica as drug delivery systems and adjuvants for oral administration of drugs or vaccines. Additionally, large pore mesoporous silica materials are potential agents for the treatment of obesity.

This dissertation focuses on utilization of poly(N-isopropylacylamide) (pNIPAm) based mirogels for regulated macromolecule drug delivery applications. There is particular emphasis on incorporation of stimuli responsive materials into multi-layer thin film constructs with the main goal being fabrication of highly functional materials with tunable release characteristics. Chapter 1 gives a broad overview of hydrogel and microgel materials focusing on fundamental properties of pNIPAm derived materials. Chapter 2 illustrates the progression of controlled macromolecule release from hydrogel and microgel materials and sets up the scope of this thesis work. Chapter 3 details studies on thermally modulated insulin release from microgel thin films where extended pulsatile release capabilities are shown. Chapters 4 and 5 focus on more fundamental synthesis and characterization studies of PEG and acrylic acid modified pNIPAm microgels that could ultimately lead to the design of protein loaded microgel films with tunable release characteristics. Chapter 6 illustrates fundamental macromolecule loading strategies, which could also prove useful in future protein drug delivery design using stimuli responsive networks. Chapter 7 concentrates on direct insulin release studies that probe the interaction between entrapped and freely diffusing protein and microgels. These model experiments could prove useful in design of tunable macromolecule drug release from functionally modified microgels and could aid in the tailored design of peptide-loaded microgel thin films. Chapter 8 discusses the future outlook of controlled macromolecule release from microgel based materials.

Despite advances in diagnostic procedures and treatments, the overall survival rate from cancer has not improved substantially over the past 30 years. One promising development is the encapsulation of toxic cancer chemotherapeutic reagents within biocompatible nanocomposite materials. The targeted stimuli triggered drug release restrict the toxic drugs to the tumour site, thereby reducing the effects of “free drug” on healthy tissues. One of the most versatile and safe materials used in medicine are iron oxide nanoparticles. This project describes the development of several formulations based on magnetite nanoparticles for drug delivery applications. Utilising magnetic nanoparticles in drug delivery systems allowed for the synergistic effects of hyperthermia and heat triggered drug released. The drug delivery systems developed in this project include magnetoliposomes, magnetic micelles, mesoporous silica-magnetite core-shell nanoparticles, liposome capped mesoporous silica-magnetite core-shell nanoparticles (protocells) and polymer capped mesoporous silica-magnetite core-shell nanoparticles. The drug loading and release profiles of the developed nanomaterials were assessed using two different anticancer drugs; Mitomycin C (MMC) and Doxorubicin (DOX). The drug loading content and drug loading efficiency for different nanocomposites ranged from 0.48 to 10.30% and 16.16 to 85.85%, respectively. Drug release profiles were studied in vitro at 37°C at pH 5.5 and pH 7.4 and at hyperthermia elevated temperature of 43°C to evaluate the effects of pH and temperature on the release profiles. An AC magnetic field with frequency of 406 kHz and variable field of up to 200 G was used to induce magnetic heating and keep the temperature within hyperthermia treatment range. Compared to uncapped mesoporous silica nanoparticles capping the mesopores of the silica nanoparticles with liposome or polymer reduced the drug release by 52.7% and 41.5%, respectively. The efficacy of doxorubicin-containing nanoparticles were evaluated in vitro against breast cancer and glioblastoma cell lines where different formulations demonstrated comparable or increased cytotoxicity compared to free drug. The cells treated with DOX loaded nanoparticles and hyperthermia demonstrated up to 89% lower viability compared to cells treated with free DOX. Silica coated magnetic nanoparticles were also used as enzymes (Pseudomonas Fluorescens Lipase (PFL) and Candida Rugosa Lipase (CRL)) supports in catalysis reactions. The enzymes were immobilised onto nanoparticles through physical adsorption and chemical bonding. The immobilised lipases were used in hydrolysis of pNPP and hydrolysis of cis-3,5-diacetoxy-1-cyclopentene to investigate the catalytic activity of the immobilized enzymes compared to free enzymes. The results indicated that free lipases provided slightly higher conversion than immobilised lipases in the first cycle however, the immobilised lipases were easily recycled and reused in sequential cycles which provides higher total yield per mg of lipase. The chemically immobilised lipase exhibited good reusability without loss of its activity in sequential cycles, however the physically adsorbed lipase showed reduced activity which could be explained by loss of enzyme during recycling between successive reactions. The CRL lipase activity were further assessed in the presence of an AC field where the results showed that exposure to the AC magnetic field resulted in increased lipase activity. The effect of reaction temperature on immobilised lipase activity were studied by performing the hydrolysis of cis-3,5-diacetoxy-1-cyclopentene at two temperatures of 25°C and 37°C where it was observed that both lipases exhibited higher activity at higher temperature which could be due to the fact that for PFL and CRL the optimum temperature is close to 37°C.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2003.
Includes bibliographical references.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
The method by which a drug is delivered can have a significant effect on the drug's therapeutic efficacy. Pulsatile delivery of certain drugs and molecules (such as hormones) has been shown to more efficacious than continuous delivery, as the fluctuation in concentration levels in vivo more closely mimics the natural physiological processes of the human body. However, there is a shortage of systems that are capable of delivering drugs in this manner, particularly if it is desired to have a self-contained system that does not require external stimulation to trigger device function. The objectives of this thesis were to design, fabricate, test, and characterize a biodegradable polymeric microreservoir device that is capable of delivering multiple pulses of drugs in a reproducible manner. This polymeric microreservoir device contains an array of reservoirs that are each covered by a thin membrane of a degradable polymer. Control over the release of drugs from the device was achieved by changing the molecular weight of the reservoir membranes. The current prototypes have 36 reservoirs, but the size and geometry of the polymeric chip could be designed to optimize device performance depending on the application for which it will be used. Changing the membrane materials or thicknesses could change the time at which the chemicals are released from the reservoirs. Each reservoir on the device could potentially have a different set of membrane characteristics, enabling release of the contents of each reservoir at a different time. A fabrication process for these devices was developed, that consists of two compression-molding steps, followed by microinjection of the reservoir membranes from solution and subsequent drying of the membranes under vacuum and elevated temperature. The devices are then loaded with the drugs to be released and sealed at room temperature. This fabrication process avoids exposure of the drugs to solvents and high temperatures that may adversely affect their stability. Further, the compression-molding process used to fabricate the main body of the device, as well as minimal solvent used in the fabrication of the reservoir membranes, were designed to minimize adverse effects upon in vivo implantation due to residual solvent. Poly(L-lactic acid) was selected as the component material for the device substrate, while
(cont.) the reservoir membranes were made from copolymers of poly(lactic-co-glycolic acid) having varying molecular weights. The degradation behaviors of these materials have been extensively studied both in vitro and in vivo, and they have been shown to be quite biocompatible. Studies showed that the degradation of the reservoir membranes in vitro and subsequent release times of chemicals from the reservoirs is a function of both the membrane thicknesses and environmental temperature. Proof-of-principle release studies showed up to four pulses of radiolabeled molecules (¹⁴C-dextran, ³H-heparin, and ¹²⁵I-HGH) from single devices, both with one chemical per device (four pulses per chemical) as well as two chemicals per device (two pulses per chemical). Bioactivity measurements showed that heparin released from the devices in vitro retains activity up to at least 143 days ...
by Amy Catherine Richards Grayson.
Ph.D.