Date of Award
Doctor of Philosophy (PhD)
Kris Noel Dahl
The immune system is composed of a network of cells that are precisely regulated to protect the body from infection. Abnormal activity of this cellular network can result in numerous diseases and disorders including chronic inflammation, rheumatoid arthritis, atherosclerosis, and cancer. Modulation of immune cells via the targeted delivery of immunologically active compounds has the potential to redirect the immune response and restore health. The unique nanostructure and properties of single wall carbon nanotubes (SWCNTs) are well-suited for cellular applications particularly in the manipulation of immune cell function. SWCNTs must be properly functionalized to maintain their inherent properties and to provide control over their uptake, processing, and delivery. This thesis focuses on understanding the macrophage cellular response to SWCNT-protein complexes and engineering the SWCNT-protein complex interface to build new functionalities that preserve inherent SWCNT properties while enabling targeting and delivery applications. Kinetic parameters governing the uptake of SWCNT-protein complexes in macrophages are determined using Raman spectroscopy. The cellular inflammatory activity level is found to contribute more to uptake than different SWCNT interfaces. The subcellular concentrations and distribution of SWCNT-protein complexes processed by macrophages are revealed in the context of aggregation state. Short SWCNTs-protein complexes are found to be concentrated in highly bundled regions, whereas long SWCNTs-protein complexes and SWCNTs in fibroblasts were not. Protein structure is further engineered to direct the subcellular localization of SWCNT-protein complexes in cells. A native cellular protein is engineered with a favorable structure for SWCNT dispersion and an exposed nuclear localization sequence for subcellular targeting to the nucleus. Finally, non-covalent SWCNT-protein interactions are tuned to enable SWCNT loading and delivery of molecules within cells. Delivery is achieved with chemotherapeutic and immunosuppressive drugs resulting in enhanced anti-proliferative and anti-inflammatory effects compared to non-complexed drugs. The scientific discoveries reveal important information about macrophage uptake and processing of SWCNTs that may be used to probe cell behavior or develop delivery approaches for therapeutic applications. The strategies developed to create excellent SWCNT dispersions with tailored functionalities through protein modifications may be used generally by other researchers to initiate new ways to modulate cellular response with nanomaterials.
Boyer, Patrick D., "Single Wall Carbon Nanotube–Protein Complexes and Immune Cells: Uptake, Processing, and Targeted Delivery" (2015). Dissertations. 569.