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.

Mesoporous silicates are excellent materials for supported catalysis due to their ease of functionalization, tunable pore size and high surface areas. Mesoporous silicates have been utilized in a variety of applications such as drug delivery scaffolds and catalyst supports. Functionalization of the surface can be achieved by either grafting of alkoxy silanes or co-condensation of the organosilane with the inorganic silica source. My research in this area can be divided into two components. In the first, we address the significant issue of metal contamination after reactions that are catalyzed by transition metals. In the second, we examine the design of new catalysts based on organic/inorganic composites. Ruthenium catalyzed processes such as olefin metathesis or asymmetric hydrogenation, are often underutilized due to the difficulty of removing the ruthenium by-products. Attempts to remove ruthenium involve treating the solution with a scavenging reagent followed by silica chromatography. Often these scavenging agents are expensive phosphines or toxic agents like lead tetra-acetate. SBA-15 functionalized with aminopropyl triethoxysilane displays a high affinity for ruthenium. Furthermore, it can be utilized to remove ruthenium by-products from olefin metathesis or hydrogenation reactions without the need for silica chromatography. We have also prepared sulfur-functionalized mesoporous silicates that have a high affinity for palladium. The materials after loading prove to be active catalysts for a variety of palladium catalyzed processes such as Suzuki-Miyaura and Sonogashira couplings. The catalysts are recyclable with moderate loss of activity and structure, depending on the method of incorporation of the thiol. We have characterized the as-synthesized and used catalysts by nitrogen sorption, TEM, X-ray photoelectron spectroscopy (XPS) and a variety of homogeneity tests were performed on the catalysts. Periodic mesoporous organosilicates (PMOs) are a well known class of inorganic-organic hybrid materials. The majority of PMOs prepared utilize simple organic bridges such as ethyl, phenyl or biphenyl. The use of a chiral organic bridging group, such as BINAP, allows the synthesis of chiral PMOs with possible applications in catalysis and separation science. The synthesis of a triethoxysilyl functionalized BINAP as well as its incorporation into PMO materials with 4,4’-bistriethoxysilyl biphenyl or tetraethylorthosilicate as co-silica sources are described. / Thesis (Ph.D, Chemistry) -- Queen's University, 2009-04-20 10:49:13.443

De part leurs propriétés physiques et chimiques, les nanoparticules de silice mésoporeuses (MSNs) sont de bonnes candidates pour la délivrance de principes actifs. Cependant, leurs toxicités et leurs devenirs intracellulaires sont largement méconnus. Au cours de ces travaux, nous avons étudié la cytotoxicité et l’endocytose de MSNs. Nous avons montré que les MSNs peuvent être endocytées par une variété de lignées cellulaires et par des astrocytes de rat en culture sans signe apparent de cytotoxicité importante. Ces nanoparticules ne présentent pas une toxicité observable in vivo chez des souris. Après avoir montré que l’endocytose des MSNs s’effectue par la voie des puits de clathrines, nous avons procédé à la délivrance intracellulaire d’une protéine. Nous avons montré un échappement des lysosomes de cette protéine grâce aux MSNs. En couplant l’acide folique aux MSNs, les cellules tumorales ont été ciblées. Lors de ces études, nous avons également montré que l’un des tests les plus utilisés en toxicologie surestime la cytotoxicité des MSNs. Cette surestimation est due à une modification du trafic intracellulaire. Nos travaux ont montré que les MSNs sont endocytés sans nuire à la viabilité cellulaire, ce qui nous a permis de réaliser les premiers essais de délivrances de principes actifs avec nos nanoparticules. / Due to their physical and chemical properties, the mesoporous silica nanoparticles (MSNs) are good candidates for drug delivery applications. However, their toxicity and their intracellular trafficking remain unclear. During these works, we studied the cytotoxicity and the endocytosis of MSNs. We showed that the MSNs can be internalised by a variety of cell lines and rat astrocytes in culture without visible sign of important cytotoxicity. These nanoparticles did not present an observable in vivo toxicity in mice. Then we showed that the endocytosis of the MSNs was made by the clathrines coated pits and we proceeded to the intracellular delivery of a protein. We showed an escape of the lysosomes of this protein due to MSNs. Such an internalised protein escaped from lysosomes under the effect of MSNs. After linking folic acid to MSNs, we are able to target tumoral cells with these nanoparticles. During the preceding studies we observed that one of the most used tests in toxicology overestimated the cytotoxicity of MSNs because the latter nanoparticles modified intracellular traffic. Our works showed that the MSNs are internalized without damaging the cellular viability and we made the first experiments of drug delivery using our nanoparticles.

Resumo: A sílica mesoporosa do tipo MSU-4 foi sintetizada a partir do agente direcionador de estrutura Tween 20, utilizado como molde, e do precursor inorgânico tetraetilortosilicato (TEOS). Estruturas mesoporosas tem sido aplicadas em estudos luminescentes por apresentarem alto índice de organização, grande área superficial e distribuição regular de tamanho de poros. Nesse trabalho a sílica mesoporosa foi funcionalizada com 3-aminopropiltrietoxisilano (APTES) para aplicação luminescente. A sílica mesoporosa funcionalizada foi caracterizada por difração de raios-X a baixo ângulo (SAXS), espectroscopia no infravermelho (FT-IR) e adsorção e dessorção de nitrogênio (BET). O material luminescente foi preparado pela formação do complexo [Eu(tta)3] em meio metanólico e impregnado nos canais da sílica mesoporosa. Para a impregnação, o íon Eu3+ foi primeiramente encapsulado na sílica e posteriormente foi adicionado o ligante 2- tenoiltrifluoroacetona (tta). Esse procedimento foi realizado para as sílicas lavada, calcinada e funcionalizada. Uma amostra de sílica funcionalizada foi preparada com a impregnação do complexo já pronto. Todas as amostras foram caracterizadas por espectroscopia luminescente. O estudo espectroscópico foi realizado à temperatura ambiente e os espectros de excitação mostraram a absorção de energia pelo ligante tta na faixa do ultravioleta. Os espectros de emissão mostraram as transições características do íon Eu3+, dos estados de maior energia 5D0 para os de menor energia 7F0-4. Foi observado que a transferência de energia do ligante para o íon Eu3+ foi eficiente. A transição hipersensitiva 5D0→7F2 mostrou o efeito das diferentes superfícies da matriz de sílica. PALAVRAS CHAVE: Sílica mesoporosa, luminescência, európio. / Abstract: MSU-4 type mesoporous sílica has been synthesized with polyoxyethylenesorbitan monolaurate (Tween 20) as structure-directing agent (MTS) as a template and tetraethyl orthosilicate Si(OEt)4 (TEOS) as silica source. The mesoporous structures have a wide application in the luminescence study because of their organization, large surface area, and size of pores. In this work, MSU-4 mesoporous silica was functionalized with 3-amino-propyl-triethoxysilane (APTES) for luminescence applications. Mesoporous silica and amino-functionalized silica was characterized by small-angle X-ray scattering (SAXS), infrared spectroscopy (FT-IR) and nitrogen adsorption/desorption isotherms at 77 K (BET). A luminescent material was prepared by formation of the complex Eu(tta)3 in methanolic medium within the channels of MSU-4 type ordered mesoporous silica. Using simple wet impregnation methods, the europium ion was first encapsulated followed by ligand 2-thenoyltrifluoracetonate (tta) addition. This process it was done for washed, calcined and functionalized mesoporous silica. Analogous one sample of functionalized silica was impregnated with the complex already ready. All samples were characterized by photoluminescence spectroscopy. The spectroscopy studies in room temperature showed the energy absorption of the ligand range ultraviolet in excitation spectra. The emission spectra this materials displayed the typical Eu3+ intra-4f6 lines ascribed to transitions between the 5D0,1 excited states and the ground multiplet (7F0-4). Negligible emission from the organic part of the encapsulated species was observed, indicating that energy transfer from the ligands to the Eu3+ ion was quite efficient. The hypersensitive 5D0→7F2 line showed the mesoporous silica effect in luminescence europium chelate. / Orientador: Marco Antonio Utrera Martines / Coorientador: Gustavo Rocha de Castro / Banca: Cláudio Luiz Carvalho / Banca: Ademir dos Santos / Mestre

Primarily concerned with manipulation and study of matter at the nanoscale, the concept of nanoscience encompasses ideas such as nanomaterial synthesis, characterization, and applications to modern scientific and societal problems. These problems encompass a broad range of issues such as energy storage and conversion, medical diagnostics and treatment, environmental remediation and detection, carbon economy and as well as many others. Silica nanoparticles of porous morphology have broad application to many of these issues. In particular, the utility of silica nanoparticles is facilitated by their large intrinsic surface area, tunable surface chemistry, and synthetic variability in both their size and morphology. This facilitates applications to these problems. However, extensive characterization and deeper understanding is needed before full implementation in key applications can be realized. The work described in this thesis aims to explore fundamental and applied characterization of silica nanoparticles that might be used in biomedical and environmental applications. Fundamental studies of functionalized nanomaterials using NMR spectroscopy reveal complex, dynamic phenomena related to-and ultimately deriving from-the intrinsic and/or modified surface chemistry. Applied studies of nanomaterial-biological interfaces demonstrate free radical chemistry as dominating the toxic response of the materials when exposed to biological systems of interest. Characterization of protein adsorbed on the interface reinforces the ubiquitous nature of protein adsorption on nanomaterial surface in biological and environmental media. Overall, this work illuminates and highlights complex changes that take place in aqueous solution for silica nanoparticles of varied morphology and surface chemistry.

<p>The work presented in this thesis has been focus on developing the idea of mesoreactor based on mesoporous silica SBA-15. SBA-15 is a mesoporous material with highly ordered pore structure and tailorable pore sizes with narrow sizes distribution. SBA-15 has been utilized to provide reaction sites for electroless copper deposition and the support of the synthesized copper nanoparticles. Oxidation processes have been conducted in order to improve the weak ion-exchange capability of as-synthesized silica surfaces. The efficiency of oxidation processes have been studied through various oxidizing agents and time. The surface treatments of mesoporous silica have been proofed to affect the distribution of the nanoparticles. Copper nanoparticles of 5 nm with narrow size distribution have been synthesized without the use of any capping agents and are homogeneously embedded in the silica matrix.</p>

This dissertation is focused on synthesis, characterization and formation mechanism of anionic-surfactant-templated mesoporous silica (AMS). Structural control mechanisms of AMS are investigated. First, different ionization degree of anionic surfactant affected by the acidity or alkalinity of the synthesis system gives rise to different charging density of micelles and therefore determines the organic/inorganic interface curvature, producing mesophases from cage-type to cylindrical, bicontinuous and lamellar. Second, mesocage/mesocage electrostatic repulsive interaction affects the formation of cage-type mesostructure, which is derived from a full-scaled synthesis-field diagram of AMS. The mesocage/mesocage interaction changes with charge density of mesocages and gives rise to their different packing manners. Third, the structural properties of AMS materials could be tuned by molecular features of surfactant and co-structure-directing agent (CSDA). The pore size of AMS is found to be controlled by alkyl chain length, ionization degree of surfactant and the CSDA/surfactant ratio. Alkyl chain length of surfactant determines size of micelles and thus mesopores. Larger ionization degrees of anionic surfactant give rise to smaller pore sizes due to thermodynamic coiling of alkyl chains of surfactant. The hydrophobic interactions between the pendant organic groups of CSDA on the silica wall and the hydrophobic core of the micelles drive a contraction of the mesopores. A mesoporous silica with novel bicontinuous cubic Pn-3m structure has been prepared using a diprotic anionic surfactant. 3d-reconstruction of the structure shows that it is bicontinuous composed of an enantiomeric pair of 3d mesoporous networks that are interwoven with each other, divided by a D surface. Inverse replication suggests the possible presence of ordered complimentary micropores in the material.

The work presented in this thesis has been focus on developing the idea of mesoreactor based on mesoporous silica SBA-15. SBA-15 is a mesoporous material with highly ordered pore structure and tailorable pore sizes with narrow sizes distribution. SBA-15 has been utilized to provide reaction sites for electroless copper deposition and the support of the synthesized copper nanoparticles. Oxidation processes have been conducted in order to improve the weak ion-exchange capability of as-synthesized silica surfaces. The efficiency of oxidation processes have been studied through various oxidizing agents and time. The surface treatments of mesoporous silica have been proofed to affect the distribution of the nanoparticles. Copper nanoparticles of 5 nm with narrow size distribution have been synthesized without the use of any capping agents and are homogeneously embedded in the silica matrix.

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.

There is an increasing demand for materials that are physically robust, easily recovered, and able to perform a wide variety of chemical functions. By combining hard and soft matter synergistically, organic-inorganic hybrid materials are potentially useful for a number of applications (e.g. catalysis, separations, sensing). In this respect, organic/ordered mesoporous silica (OMS) hybrids have attracted considerable attention, with an increasing emphasis on complex organic moieties achieved through multi-step reactions and polymerizations. It is on this front that we have focused our work, specifically in regard to polypeptides. Polypeptides are well suited organic components for hybrids as they provide a wide range of possible side chain chemistries (NH2, -SH, -COOH, -OH, etc.), chirality, and have conformations that are known to be responsive to external stimuli (pH, electrolytes, solvents, etc.). Our work has shown that N-carboxyanhydride chemistry offers a facile single step approach to the incorporation of dense polypeptide brushes in OMS. Modifying the initiator loading, pore size, pore topology, and monomer identity significantly impacted the properties of the obtained composites and peptide brush layers. Extending this work, a synthesis paradigm for preferentially grafting poly-L-lysine to the external and internal surfaces of SBA-15, a widely used OMS material, was developed. We observed that the pores of these hybrids could be opened and closed by the reversible swelling of the polypeptide layer. Similarly, novel bifunctional hybrids were synthesized by grafting polypeptides to the external surface of monodisperse OMS spheres that contain a thiol-functionalized core. The accessibility of the internal thiols to a fluorescent dye shows the potential of these hybrids for applications such as controlled uptake/release.