Date of Award
Doctor of Philosophy (PhD)
Photodynamic therapy (PDT) provides efficient tumor killing through the generation of reactive oxygen species (ROS) from the optical excitation of a photosensitizer (PS). Furthermore, this mechanism is highly immune stimulating, providing systemic tumor immunity with a reduction in metastasis. However, these materials had previously been limited by their dependence upon external light sources, allowing treatment of only laser-accessible malignancy. With the recent development of photosensitized radiation stimulated therapy (PRaST) this depth dependence is broken through co-localization of radionuclides and semiconducting photosensitizers. This dissertation focuses on the enhancement of titanium dioxide (TiO2) based PRaST agents through understanding of TiO2 material parameters as well as adsorbent surface coatings to enhance therapeutic outcomes. TiO2 has several known crystal phases and can be generated from atomic clusters to micrometer sizes. To improve its therapeutic potential, we first investigated the effect these parameters had on its primary constraints, namely ROS generation and biodistribution, finding an interplay between 5 nm and 25 nm TiO2 crystal domains. Furthermore, we sought to overcome the central tumor resistance mechanism to PDT, that of oxygen dependence. ROS generation from molecular PS traditionally use NIR, optical excitation of electrons whose energy is then transferred to associated oxygen. Nanoscale TiO2 can use both electron and hole intersystem crossing, which generates ROS from adsorbed oxygen and water. To enhance this pathway, we investigated the ability of chromium VI ions to increase TiO2 hole flux as well as the ability of adsorbed dichromate to act as an oxygen independent metallo-therapeutic. Finally, we develop a polymer stabilized perfluorocarbon nanoemulsion able to be tracked with near-infrared fluorescent imaging and increase the oxygenation of hypoxic tumor tissue for the duration of PRaST. This can help to both boost ROS generation and normalize tumor microenvironments. Combined these developments point to new nano-design strategies to improve upon novel PRaST, optimizing the particles to both improve ROS generation and decrease tumor resistance.
Abdel Kareem Azab, Gregory M. Lanza, Srikanth Singamaneni, Hong Chen,