Enhancing Magnetic Iron Oxide Nanoparticle Targeting to Brain Tumors.

Brain tumors are highly lethal, most often resulting in a terminal prognosis. Today's standard-of-care has not significantly altered patient survival time. The status quo indicates the need for a more targeted, multi-functional therapeutic approach. Nanotechnology has been implicated as a potential magic bullet drug carrier solution to cancer, with magnetic iron oxide nanoparticles (MNPs) representing a unique, magnetically responsive type of nanomaterial. MNPs have been targeted to brain tumors by applying an external magnetic field to lesions. The short circulation times of preferred MNPs, though, limits their availability for targeting, and, thus, tumor delivery. If plasma residence were enhanced, the question then arises: would targeting efficiency improve? This dissertation aimed to develop long-circulating MNPs suitable for enhanced magnetic brain tumor targeting. Aminosilane (A) and cross-linked starch coated, polyethylene glycol (PEG) conjugated MNP candidates were synthesized using N-hydroxysuccinimide chemistry and characterized. Candidates were similar in size (140--190 nm) and PEG content, (up to 1.5 mol %) and deemed magnetically suitable for targeting. Candidates were subjected to in vitro reticuloendothelial system simulations to predict long-circulating behavior in vivo. Unlike the A-platform, cross-linked starch PEG-MNPs (D5/D20) performed well in vitro showing sustained size stability in cell culture medium and up to 10-fold reduced uptake in RAW 264.7 macrophages, when compared to previously studied starch-coated MNPs (D). Simulations predicted improved circulation behavior, with intravenously administered D5/D20 (12 mg Fe/kg) showing up to an estimated 150-fold increase in tumor exposure over D in 9L-glioma bearing rats. Validated electron spin resonance methodology was used to study biodistribution of D5/D20 in tissues of elimination. MNP concentrations in the spleen were high, and, unexpectedly, appeared attenuated in the liver. Improved exposure of MNPs to rat 9L-glioma lesions resulted in enhanced magnetic brain tumor targeting (t=1 hr) with up to 1.0% injected dose (ID)/g tissue (200 g animal) delivery achieved, a 15-fold improvement over targeted D (0.07% ID/g tissue). Magnetic resonance imaging confirmed targeting enhancements. Results achieve proof-of-concept that long-circulating MNPs permit enhanced magnetic targeting of nanoparticles to brain tumors, warranting further development of the materials and strategy studied.PhDHealth and Environmental SciencesPharmaceutical sciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127181/2/3458791.pd