| Photodynamic therapy (PDT) has emerged as one of the important minimally invasive therapeutic modalities for breast cancer, which employs the combination of light and photosensitizer to induce the formation of cytotoxic reactive oxygen species (ROS) for cell destruction. Despite its multifaceted advantages, PDT has not yet become a mainstream cancer intervention modality primarily due to the insufficient therapeutic efficacy and specificity of currently available photosensitizers, as well as the limited light penetration to reach tumor tissues in the deep location. Recognition of these challenges has greatly motivated the efforts to adopt nanomaterials for improving current PDT. Among various nanomaterials, gold nanoparticles (Au NPs), due to their superior optical and surface plasmonic resonance (SPR) properties, have received particular attention as promising enhancers to PDT by promoting the generation of ROS from photosensitizer upon light irradiation. This doctoral dissertation explores the utility of gold nanostructures for PDT with enhanced therapeutic efficacy, improved specificity, increased tissue penetration depth. In particular, the correlation between critical physiochemical properties (surface charge, shape, morphology, surface functionalization, intracellular destination) of gold nanostructures and their corresponding PDT effects was established. Given that mitochondria are the primary sites for photodynamic reaction, Au NPs functionalized with mitochondria-targeting domain have demonstrated a significant elevation of ROS formation with enhanced therapeutic efficacy and selective destruction of breast cancer cells in 5-aminolevulinic acid (5-ALA)-PDT. To address the light penetration limitation associated with current PDT, novel colloidal Au nanorings (Au NRs), with unique SPR properties at near-infrared (NIR), were employed to enhance the formation of singlet oxygen (1 O2) under NIR light irradiation for increased destruction of human breast cancer cells in the 5-ALA-PDT. In recognition of the presence of "hotspots" at the junction of aggregated particles, intracellular induction of Au NP aggregate formation was enabled by sequentially incubating the breast cancer cells with positively charged Au NPs and negatively charged Au NPs, which led to further improvement of the therapeutic efficiency of PDT. To better evaluate the PDT efficiency and ascertain the enhanced effects of Au NPs in the pathophysiologically relevant tumor microenvironments, an in vitro three-dimensional (3D) breast cancer tissue model based on a customized microfluidic culture system was established and utilized to evaluate PDT under various treatment conditions. |
