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Date of Award
Doctor of Philosophy (PhD)
Multiple myeloma (MM) is a hematologic malignancy of the antibody-producing plasma cells in the bone marrow. Most patients with MM respond to initial treatments, but nearly all will eventually relapse and die from this progressive disease. Although the mechanisms of cancer proliferation and resistance to conventional therapies are still being elucidated, it is clear that new therapeutic approaches are needed to increase treatment efficacy and prevent relapse with limited off-target toxicity. Cerenkov radiation induced therapy (CRIT) is a light-based cancer therapy that generates cytotoxic ROS by exposing nanophotosensitizers, including TiO2 nanoparticles, to ultraviolet (UV) light in the Cerenkov radiation (CR) emitted by positron emission tomography (PET) radiopharmaceuticals. CR is generated as the PET radionuclides circulate throughout the body and emit positrons that travel faster than the speed of light within the body. Nanophotosensitizers that have been targeted to cancer cells absorb this UV light and become excited, generating an electron and hole pair on the surface of the nanoparticle. This electron and hole react with water and oxygen to produced cytotoxic hydroxyl and superoxide radicals, which cause localized cancer cell death. The primary focus of this work was the development of novel CRIT-based nanoparticle constructs for the treatment of MM. The synthesis, characterization, functionalization, and medical imaging of these nanoparticle constructs was also explored in detail. TiO2 nanoparticles and their composites were characterized by size, aggregation behavior, and composition, using a suite of instruments that included a single particle inductively coupled plasma mass spectrometer (SP-ICP-MS) and a tandem scanning mobility particle sizer and inductively coupled plasma optical emission spectrometer (SMPS-ICP-OES). It was found that the stability of TiO2 nanoparticles depends on many characteristics of the primary particle, including its size, chemical composition, surface charge, and surface chemistry. Changes in the attraction and repulsion forces between nanoparticles are also critical and are affected by pH, nanoparticle concentration, and the concentrations and types of dissolved matter. The stability data was then used to guide the controlled functionalization of TiO2 nanoparticles with the glycoprotein transferrin (Tf), achieved using an electrospray system. Monodisperse nanoscale droplets containing TiO2 nanoparticles and Tf dried during flight, coating the proteins onto the surface of the metal oxide nanoparticles. This functionalization method improved the nanoparticles’ stability in suspension, enhanced their targeting of the Tf receptor, and increased their toxicity to MM1.S cancer cells during CRIT. This work also explored the synthesis of composite nanoparticles of TiO2 and other metals for CRIT constructs that can be imaged using magnetic resonance imaging (MRI) and PET techniques. Extremely small (<4 nm) iron oxide nanoparticles (IONPs), mostly embedded on the surface of TiO2 nanoparticles, were synthesized by flame spray pyrolysis. The spatially separated IONPs exhibited reduced magnetic coupling, which provided enhanced T1 MRI contrast. The relaxation of the composite was found to depend on the iron to titanium ratio and IONP size. An IONP-TiO2 composite containing 5 percent iron by weight was found to have a relaxation similar to that of a common clinical MR imaging contrast agent, DTPA-Gd. An all-in-one photosensitizer construct was also synthesized using TiO2 nanoparticles as photosensitizers, the Tf as a targeting ligand, and chemisorbed 89Zr as a CR and PET contrast source. The 89Zr-TiO2-Tf construct showed excellent ROS generation in a cell-free model, in an MM1.S human MM cell model, and in a 5TG-M murine myeloma cell model. PET/x-ray computed tomography (PET/CT) imaging and biodistribution studies of treated mice showed preferential uptake of 89Zr-TiO2-Tf in bone, which reduced MM disease progression.
Samuel Achilefu, John Fortner, Monica Shokeen, Fuzhong Zhang,
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