Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Biomedical and Pharmaceutical Sciences
Scientific areas have utilized the exclusive qualities of nanomaterials for medicine, diagnostics, drug delivery, tissue engineering and environmental protection. Inorganic metal nanoparticles such as gold and copper have been widely studied in the past decades. Due to the strong and tunable surface plasmon resonance (SPR), nanostructures including nanoshells, nanorods, nanocages, and hollow nanospheres exhibit strong optical absorption at near-infrared (NIR) wavelengths (650–900 nm), resulting in resonance and transfer of thermal energies to the surrounding tissue to raise the temperature. The absorbance of NIR light is desirable because it minimizes thermal injury to normal tissues while providing optimal light penetration. The efficient photothermal energy transfer effect by inorganic metallic nanoparticles such as gold has been widely used for photothermal ablation of tumor tissues, as well as drug delivery system for small molecules like protein, antibodies, DNAs, and small interfering RNAs by NIR laser triggered-release.
Even though different kinds of gold nanoparticles have a great advantage on the photothermal transaction and are promising for clinical applications, they are nonbiodegradable, raising concerns regarding their short/long-term metabolism and safety. Tail vein injections of polyethylene glycol (PEG)-coated gold nanoparticles have been reported to induce two phases of toxicity concerning inflammation in the liver. The acute phase occurred immediately after administration of nanoparticles. The second phase happened at 7 days post injection when the nanoparticles become localized in the tissues, mostly in the liver and spleen after circulation in the blood. Due to multiple valences of gold, redox reaction of gold within cells can increase the levels of reactive oxygen species (ROS), which interferes with the mitochondrial membrane potential. Disturbance of the mitochondrial membrane potential after exposure to gold nanoparticles initiates an apoptotic cascade in cells.
It was also reported that three months after injection of PEG-HAuNPs, 11.4 ± 1.8 percentage of injected dose per gram (%ID/g) remained in liver, which was 70% of the amount at one-day post injection. However, three months after injection of PEG-HCuSNPs, the Cu level remaining in the liver was 1.1 ± 0.1 %ID/g, which was only 5% of the amount at 1day post injection. The Cu level in the liver decreases much faster than Au level after 1 day, indicating faster metabolism and excretion of copper nanoparticles than the gold nanoparticles.
Based on the previous research and findings, although gold nanoparticles have more efficient photothermal transfer and more potential of future clinical usage for tumor tissue ablation, they have a very slow metabolic and excretion rate, which leads to acute and chronic in vivo toxicity. These findings support the hypothesis that conjugating copper with gold nanoparticles will increase the in vivo excretion rate of gold to reduce its toxicity while retaining the more efficient photothermal transfer properties of gold nanoparticles for future clinical application.
Manuscript 1: Introduction to Metal Nanoparticles: Application in Pharmaceutical Sciences (to be submitted to Materials Chemistry and Physics) reviews the development and promising application of metal nanoparticles in pharmaceutical and biomedical industry including, but not limited to, drug delivery, in vivo imaging, in vitro diagnostics, therapeutics techniques, toxicity, etc.
Manuscript 2: Enhanced Cellular Clearance of Gold Nanoparticles by Copper Sulfide Nanoparticles Through ATP7B as Transporter. (to be submitted to ACS Nano) In this study, we use PEGylated hollow CuS nanoparticles (PEG-HCuSNPs) of ~70 nm in diameter as models to elucidate their highly efficient metabolic trafficking in mouse liver. The Cu-ATPase transporter, ATP7B efficiently facilitates removal of excess Cu ions in hepatocytes. ATP7B together with PEG-HCuSNPs-loaded lysosomes move toward the apical domains of hepatocytes to transfer Cu into the bile canaliculi through exocytosis. Moreover, primary cultured mouse hepatocytes exhibit much higher efficient copper exocytosis than primary cultured mouse Kupffer cells. Tail vein injections of polyethylene glycol (PEG)-coated gold nanoparticles have been reported to induce two phases of toxicity concerning inflammation in mouse liver. Conjugating copper with gold nanoparticles will increase the in vivo excretion rate of gold to reduce its toxicity by fast metabolism and excretion rate of copper while retaining the more efficient photothermal transfer properties of gold nanoparticles for the future clinical application.
Wang, Xiaodong, "Facilitated Excretion of Gold Nanoparticles by Copper Sulfide Nanoparticles Through the ATP7B Transporter" (2018). Open Access Dissertations. Paper 715.