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Biofunctionalized Mesoporous Silica for Controlled Release Applications
Biofunctionalized Mesoporous Silica for Controlled Release Applications
Host-Guest chemistry based on mesoporous silica materials has attracted increasing attention in the past two decades. Potential applications for these functionalized materials are in the fields of controlled drug delivery, catalysis, separation or encapsulation of functional biomolecules. The present work is focused on the synthesis of nanosized, mesoporous drug delivery devices, which are able to release a preloaded drug as a result of a certain trigger action, e.g. during the endocytosis in a cancer cell. For this purpose, several different synthesis strategies had to be developed in order to incorporate the different required functional groups within one mesoporous silica nanoparticle. A spatial separation of two different functionalities was achieved by the development of a sequential co-condensation approach. With this approach, core-shell bifunctionalized colloidal mesoporous silica could be synthesized. The obtained particles are an important prerequisite for other systems presented in this work. The applicability of the copper-(I)-catalyzed Huisgen reaction (click reaction) as mild synthetic tool for the immobilization of biomolecules in the channels of mesoporous silica was investigated. In this joint project between our group and the research group of Prof. Ernst Wagner (LMU), it was shown that a sensitive enzyme can be immobilized with this strategy in the pores of SBA-15. It was demonstrated that the recoverability and long-term stability of the active enzyme benefits from the encapsulation in the host. The well-known strong biotin-avidin interaction was used for the construction of a protease-responsive cap system for controlling the release from colloidal mesoporous silica. Fluorescein was released from the nanoparticles as a model compound for small drug molecules. In order to monitor the release, a custom-made two-compartment fluorescence cuvette was designed. Thermoresponsive opening through protein denaturation was demonstrated for temperatures higher than 90 °C. A programmable opening temperature for this concept became possible by using DNA-linkers between the silica surface and the avidin cap. It was demonstrated that the length of the double-stranded DNA controls the opening temperature of the avidin cap. This work was carried out as a join project between our group, the research group of Prof. Thomas Carell (LMU) and the baseclick GmbH. Redox-responsive drug delivery was investigated in living cells. In this context, the release of disulfide-linked, dye-labeled cystein from the core of colloidal mesoporous silica was monitored by confocal fluorescence microscopy at a single cell level, in collaboration with the research group of Prof. Christoph Bräuchle. It was shown by photoinduced endosomal rupture that the endosomal escape is a bottleneck in redox-based drug delivery. This concept was extended through the synthesis of photosensitizer-functionalized, PEGylated colloidal mesoporous silica. It was demonstrated that particle-loaded endosomes collapse under irradiation with 405 nm light and release the particles into the cytosol. In another joint project between the groups of Prof. Bein, Prof. Bräuchle, Prof. Rädler and Prof. Leonhardt together with Dr. Ulrich Rothbauer (all LMU), the novel photosensitizer-functionalized porous nanoparticles were used as carriers for the delivery of small GFP-binding antibodies from Camelidae sp. into GFP-tubulin expressing HuH7 cancer cells. Additionally, the particles were encapsulated by a supported lipid bilayer. The attached photosensitizer was shown to play a key role in the delivery mechanism. Light-irradiation was used to destroy both surrounding membranes (supported lipid bilayer and endosomal membrane). Finally, the pH-responsive release of the membrane-intercalating peptide mellitin from a mesoporous SBA-15 host was demonstrated. This was possible through the use of pH-sensitive acetal linkers. The release of the peptide was shown by the lysis of mouse erythrocytes. This work was carried out in collaboration with the group of Prof. Ernst Wagner. To summarize, mesoporous silica materials were functionalized with different biomolecules in order to generate novel materials for potential applications in drug delivery or other controlled release applications. The newly developed concepts provide a basis for future work on mesoporous silica as a powerful and versatile drug delivery platform.
Nanotechnology, Silica, Mesoporous, Click Chemistry, Controlled Release
Schloßbauer, Axel
2010
Englisch
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Schloßbauer, Axel (2010): Biofunctionalized Mesoporous Silica for Controlled Release Applications. Dissertation, LMU München: Fakultät für Chemie und Pharmazie
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Abstract

Host-Guest chemistry based on mesoporous silica materials has attracted increasing attention in the past two decades. Potential applications for these functionalized materials are in the fields of controlled drug delivery, catalysis, separation or encapsulation of functional biomolecules. The present work is focused on the synthesis of nanosized, mesoporous drug delivery devices, which are able to release a preloaded drug as a result of a certain trigger action, e.g. during the endocytosis in a cancer cell. For this purpose, several different synthesis strategies had to be developed in order to incorporate the different required functional groups within one mesoporous silica nanoparticle. A spatial separation of two different functionalities was achieved by the development of a sequential co-condensation approach. With this approach, core-shell bifunctionalized colloidal mesoporous silica could be synthesized. The obtained particles are an important prerequisite for other systems presented in this work. The applicability of the copper-(I)-catalyzed Huisgen reaction (click reaction) as mild synthetic tool for the immobilization of biomolecules in the channels of mesoporous silica was investigated. In this joint project between our group and the research group of Prof. Ernst Wagner (LMU), it was shown that a sensitive enzyme can be immobilized with this strategy in the pores of SBA-15. It was demonstrated that the recoverability and long-term stability of the active enzyme benefits from the encapsulation in the host. The well-known strong biotin-avidin interaction was used for the construction of a protease-responsive cap system for controlling the release from colloidal mesoporous silica. Fluorescein was released from the nanoparticles as a model compound for small drug molecules. In order to monitor the release, a custom-made two-compartment fluorescence cuvette was designed. Thermoresponsive opening through protein denaturation was demonstrated for temperatures higher than 90 °C. A programmable opening temperature for this concept became possible by using DNA-linkers between the silica surface and the avidin cap. It was demonstrated that the length of the double-stranded DNA controls the opening temperature of the avidin cap. This work was carried out as a join project between our group, the research group of Prof. Thomas Carell (LMU) and the baseclick GmbH. Redox-responsive drug delivery was investigated in living cells. In this context, the release of disulfide-linked, dye-labeled cystein from the core of colloidal mesoporous silica was monitored by confocal fluorescence microscopy at a single cell level, in collaboration with the research group of Prof. Christoph Bräuchle. It was shown by photoinduced endosomal rupture that the endosomal escape is a bottleneck in redox-based drug delivery. This concept was extended through the synthesis of photosensitizer-functionalized, PEGylated colloidal mesoporous silica. It was demonstrated that particle-loaded endosomes collapse under irradiation with 405 nm light and release the particles into the cytosol. In another joint project between the groups of Prof. Bein, Prof. Bräuchle, Prof. Rädler and Prof. Leonhardt together with Dr. Ulrich Rothbauer (all LMU), the novel photosensitizer-functionalized porous nanoparticles were used as carriers for the delivery of small GFP-binding antibodies from Camelidae sp. into GFP-tubulin expressing HuH7 cancer cells. Additionally, the particles were encapsulated by a supported lipid bilayer. The attached photosensitizer was shown to play a key role in the delivery mechanism. Light-irradiation was used to destroy both surrounding membranes (supported lipid bilayer and endosomal membrane). Finally, the pH-responsive release of the membrane-intercalating peptide mellitin from a mesoporous SBA-15 host was demonstrated. This was possible through the use of pH-sensitive acetal linkers. The release of the peptide was shown by the lysis of mouse erythrocytes. This work was carried out in collaboration with the group of Prof. Ernst Wagner. To summarize, mesoporous silica materials were functionalized with different biomolecules in order to generate novel materials for potential applications in drug delivery or other controlled release applications. The newly developed concepts provide a basis for future work on mesoporous silica as a powerful and versatile drug delivery platform.