Magnetic Nanoparticles for Targeted Cancer Theranostics
Stephen, Zachary R.
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Nanotechnology has given scientists new tools for the development of advanced materials for the detection, diagnosis and treatment of disease. Superparamagnetic iron oxide nanoparticles (SPIONs) in particular have been extensively investigated as novel magnetic resonance imaging (MRI) contrast agents due to a combination of favorable superparamagnetic properties, biodegradability, and surface properties that allow modification for improved in vivo kinetics and multifunctionality. SPIONs favorable characteristics have further led to their investigation as promising theranostic agents, which combine imaging and therapeutic capabilities in a single nanovector. The combination of imaging and therapy could allow for real-time monitoring of drug delivery and the tailoring of treatment for individual patients with the promise of improved clinical outcomes for patients suffering from cancers such as glioblastoma (GBM). This dissertation is intended to address limitation of conventional clinical cancer treatment including current cancer targeting limitations and poor pharmacokinetic of hydrophobic chemotherapeutics that lead to unacceptable side effects. First, SPIONs were coated with cross-linked, redox-responsive copolymers composed of chitosan and polyethylene glycol (PEG), functionalized with cancer targeting agent chlorotoxin (CTX), and modified with O6-benzylguanine (BG), an O6-methylguanine-DNA methyltransferase (MGMT) inhibitor to improve temozolomide based treatments of GBMs. It was found that CED of the BG loaded SPION were more tolerable than free drug and increased survival 3-fold over untreated animals in an intracranial GBM mouse model. Next, analogs of BG were evaluated for their inhibitory efficacy and modified to allow for polymerization on the SPION surface via hydrazone linkages to facilitate improved drug loading and controlled drug release. Finally, a new synthesis and functionalization strategy for theranostic agents is presented that demonstrated streamlined production, allowed for great control over the display of functional moieties on the SPION surface, increased batch to batch consistency, and provided improved magnetic properties.