Inflamed Leukocyte-Mimetic Nanoparticle And Its Applications In Quantitative Inflammation Imaging
Intense and prolonged inflammation correlates with the progression of various inflammatory diseases, ranging from cancer to sepsis. Sensitive detection and quantitative examination of the site of inflammation will, therefore, produce a wideranging impact on disease diagnosis and treatment. Studies presented in this dissertation first attempt to design one nanoparticle that mimics the molecular interactions occurring between inflamed leukocytes and endothelium. To incorporate inflammation-sensitive molecular interactions, super paramagnetic iron oxide (SPIO) nanoparticles were conjugated with integrin lymphocyte function-associated antigen (LFA)-1 I domain, engineered to mimic activated leukocytes in physiology. We speculated such nanoparticles may possess selectivity toward diverse host inflammatory responses, which were then confirmed by whole body optical and magnetic resonance imaging (MRI) in vivo, in that leukocyte-mimetic nanoparticles (LMN) localized preferentially to the inflamed vasculature marked by high level of ICAM-1 within and in the invasive front of the tumor, as well as to the subcutaneous site of acute inflammation. The second part of the studies closely follow up with this finding, focusing on high resolution spatiotemporal imaging of inflammation in mice treated with systemic injection of lipopolysaccharides (LPS) to mimic systemic inflammatory response or sepsis. Diagnosis of organ-level inflammation was achieved by MR imaging of LMN. Using a novel MRI quantitative susceptibility mapping (QSM) technique for noninvasive quantification of SPIO, we observed a greater accumulation of LMN in the liver, specific to ICAM-1 induction due to LPS-induced inflammation. Overall, the amounts of organic nanoparticles estimated by QSM were in good agreement with the values measured by radioactivity, presenting the idea that spatiotemporal mapping of LMN by QSM may provide a reliable, rapid, non-invasive method for identifying organ-specific inflammation not offered by existing diagnostic techniques. Yeast surface display (YSD) has been a powerful tool in engineering the active I domain for LMN. The last part of this dissertation discusses utilizing YSD in generating new monoclonal antibody against ephrin-B2, one highly conserved antigen participating in tumor angiogenesis. Being independent investigations outside of our major focus on LMN and inflammation imaging, studies presented here demonstrate another example of molecular discoveries which are critical for future development of biomimetic nanomaterials and therapeutics.
Zipfel, Warren R.; Parker, John Stuart Leslie
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis