UCLA

The research discussed in this thesis is divided into a total of five chapters, and divided into two sections. In section one, novel silica nanomaterials are developed for biological applications. Chapter one discusses the invention and development of mesoporous silicate nanomaterial, as well as their biomedical application towards a drug delivery system to treat diseases. Chapter two highlights the exploration of combining multiple modalities to a mesoporous silica nanoparticle system, applied to both in vitro and in vivo models. In order to combine two functions into a nanoparticle system, several iterations are designed to synthesize a pH-sensitive nanovalve to be used in conjunction with transferrin, a popular targeting agent. In vitro results are very promising to improve the targeted and controlled delivery of doxorubicin, and show the first proof of concept for a multifunctional nanoparticle. Chapter three delves into the development of large pore silica nanoparticles to deliver biomolecules and utilizing the pH-sensitive biopolymer, chitosan, as a capping agent. Chitosan serves to be a promising potential capping agent, however further optimizational studies are necessary to increase the loading capacity and improve release of cargo. In section two, the practical applications of mesoporous silica nanoparticles are discussed in order to treat a variety of diseases, such as tuberculosis, tularemia, and cancer. The fourth chapter discusses the fate of the mesoporous silica nanoparticles after they are exocytosed from cells in a two-pronged approach. Cells are treated with nanoparticles are labeled with fluorescent dye and a variety of inhibitors, and monitored by fluorescence microscopy to determine the mechanism of exocytosis. Nanoparticles are synthesized with a magnetic core to be collected, and the proteins adsorbed onto the surface are analyzed by mass spectrometry to be tested as a diagnostic tool. The protein corona composition varies from the various surface charges, when incubated with A549, MCF7, or HFF cells. Proteins unique to cancer cell lines are identified, which indicate mesoporous silica nanoparticles as a promising diagnostic tool. Finally, chapter five discusses the optimization of delivering isoniazid, a small molecule antibiotic, using an acid-sensitive hydrazone bond to covalently attach the drug to the surface of the MSNs to treat tuberculosis. Two size iterations are examined (50 and 100 nm diameters), which show the differences in cellular uptake and in vivo biodistribution. We see a very effective delivery of isoniazid-loaded MSNs, which is a significant improvement when compared to the free drug in both in vitro and in vivo models.