The design and synthesis of heterogeneous core shell nanomaterials for biological applications

Abstract

Nanomaterials are a unique class of materials that operate at the same size scale as cellular structures, providing a unique advantage for the study and manipulation of biological systems. Inorganic nanoparticles, in particular, have unique physical and chemical properties associated with them that provide them a unique and powerful advantage in biological applications. For example, metal nanoparticles, most popularly gold, possess plasmonic properties which provide them with imaging, sensing, and therapeutic modalities. Magnetic nanoparticles, on the other hand, although capable of MRI imaging, are a powerful class of materials owing to their ability to respond to magnetic fields. This allows for the manipulation of biological structures in space and time, providing researchers the ability to control cell signaling and behavior. Over the recent years, researchers have sought to incorporate multiple physical properties into a single nanoparticle, creating a highly multifunctional and versatile therapeutic platform. This has led to the rise of core-shell nanoparticles, where normal core nanoparticles have an additional inorganic shell material grown over their surface. This imbues the nanoparticle with multiple materials properties, allowing for advanced and novel applications in biomedicine. The application of core-shell nanomaterials, and nanomaterials in general, in biological settings requires the careful design of the material to imbue it with properties appropriate for the application at hand. In the first third of this thesis, magnetic core gold shell nanoparticles are incorporated into a novel platform for the delivery of a potent anti-cancer peptide (ATAP), and the synergistic application of magnetic hyperthermia. To this end, we demonstrate that the MCNPs provide an ideal anti-cancer platform, circumventing the poor solubility and high IC50 of ATAP. Moreover, besides enhancing the anti-cancer properties of ATAP, the magnetic core allowed for the application of magnetic hyperthermia, which we showed to act in synergism with ATAP. Furthermore, the plasmonic gold shell allows for the facile surface functionalization of tumor targeting ligands, to imbue the system with targeted delivery. Moreover, the plasmonic gold shell allows for dark field imaging to track the delivery of the MCNPs and ATAP. In the second third of this thesis, magnetic core mesoporous silica shell nanoparticles are utilized for stem cell based gene therapy. The core shell nanoparticles in this case provide a means to deliver a heat inducible plasmid encoding TRAIL, a cancer-specific therapeutic protein. After engineering stem cells, which possess tumor homing capabilities, by delivering this plasmid using magnetic core mesoporous silica shell nanoparticles, the magnetic core can be used to apply magnetic hyperthermia. This allows for the site-specific activation of TRAIL in response to magnetic hyperthermia, which is shown to induce significant cancer cell death. In the final third of this thesis, a novel heterogeneous core shell upconversion nanoparticle architecture was developed to enhance the upconversion efficiency of the material at low power excitations. This is done by separating the photon harvesting atoms and luminescent lanthanides, to which the energy is transferred, into separate shells in an individual nanoparticle. This serves to mitigate any energy transfer away from the luminescent centers to other atoms. This architecture results in a significant enhancement in upconversion luminescence at low power excitations as compared to other UCNP architectures. Moreover, we demonstrate the utility of this novel UCNP design by constructing a sensitive UCNP FRET-based biosensor capable of detection at three orders of magnitude lower concentrations than most UCNP FRET-based biosensors. Overall, this thesis has demonstrated the design and synthesis of three multifunctional inorganic core shell nanoparticles for cancer therapy and biosensing: 1) magnetic core gold shell based anti-cancer therapy, 2) magnetic core mesoporous silica shell stem cell engineering for cancer therapy, and 3) heterogeneous core shell upconversion nanoparticles for controlling energy migration for enhanced luminescence and sensitive biodetection.