Biomedical imaging and therapy with physically and physiologically tailored magnetic nanoparticles
Khandhar, Amit Praful
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Magnetic particle imaging (MPI) and magnetic fluid hyperthermia (MFH) are emerging imaging and therapy approaches that have the potential to improve diagnostic safety and disease management of heart disease and cancer - the number 1 and 2 leading causes of deaths in the United States. MPI promises real-time, tomographic and quantitative imaging of superparamagnetic iron oxide nanoparticle (SPION) tracers distributed <italic>in vivo</italic>, and is targeted to offer a safer angiography alternative for its first clinical application. MFH uses ac-fields to dissipate heat from SPIONs that can be delivered locally to promote hyperthermia therapy (~42°C) in cancer cells. Both technologies use safe radiofrequency magnetic fields to exploit the fundamental magnetic relaxation properties of superparamagnetic iron oxide nanoparticles (SPIONs), which must be tailored for optimal imaging in the case of MPI, and maximum hyperthermia potency in the case of MFH. Furthermore, the magnetic core and shell of SPIONs are both central to the optimization process; the shell, in particular, bridges the translational gap between the optimized core and its safe and effective use in the physiological environment. Unfortunately, existing SPIONs that were originally designed as MRI contrast agents lack the basic physical properties that enable the clinical translation of MPI and MFH. In this work, the core and shell of monodisperse SPIONs were optimized in concert to accomplish two equally important objectives: (1) biocompatibility, and (2) MPI and MFH efficacy of SPIONs in physiological environments. Critically, it was found that the physical and physiological responses of SPIONs are coupled, and impacting one can have consequences on the other. It was shown that the poly(ethylene glycol) (PEG)-based shell when properly optimized reduced protein adsorption to SPION surface and phagocytic uptake in macrophages - both prerequisites for designing long-circulating SPIONs. In MPI, tailoring the surface coating reduced protein adsorption and improved colloidal stability, which were critical in retaining the magnetization relaxation properties of the SPIONs. The improvements in surface coatings enabled the use of larger SPION cores (> 20 nm core diameter), which were used to demonstrate benchmark-imaging performance in some of the world's first MPI scanners at Philips Medical Imaging and University of California, Berkeley. In MFH, it was shown for the first time that optimization of heat loss from SPIONs (W/g) is possible by tailoring the core size and size distribution for the given ac-field conditions. Biodistribution and blood circulation studies in mice showed that SPIONs accumulated primarily in the liver and spleen with minimal renal involvement, and demonstrated gradual clearance. Circulation time was evaluated using the MPI signal detected over time in blood, which offered insight on the relevant circulation time for angiography applications. In comparison with carboxy-dextran coated Resovist® SPIONs, the PEG-coated SPIONs developed in this work circulated substantially longer; furthermore, reducing the hydrodynamic diameter showed a 4.5x improvement in blood half-life. The work presented in this thesis demonstrates that the combined effort in optimizing the core and shell properties of SPIONs enhances biocompatibility and efficacy, with the <italic>in vivo</italic> studies providing critical feedback on the success (or failure) of the optimization process. Future work will entail designing functionalized SPIONs for targeting specific disease sites, which will further enable the molecular level diagnosis and therapy of diseases.