Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Andrew Tsourkas

Abstract

Radiation therapy is an important component in the treatment and management of cancer patients. Despite current advances in imaging technologies and treatment planning strategies, a major limitation persists in accurately delineating tumor from normal tissue resulting in radiation–induced damage to healthy structures. Therefore, the frequency and dose of radiation exposure is limited by the generated toxicity in healthy tissues. The use of nanoparticles for contrast–enhanced imaging could improve the accuracy of therapeutic delivery and guide radiation treatments to maximize delivery to disease target tissues while sparing adjacent normal structures. Further, advancements in radiation therapy focus on the use of radiosensitizers that are intended to enhance tumor cell killing while minimizing effects on normal tissue. We have developed multifunctional nanoplatforms, containing sub–nanometer gold and iron nanoparticles that can provide contrast enhancement using computed tomography and magnetic resonance imaging, while also serving as radiosensitizers for X–ray therapy. The effectiveness of these nanoparticles was evaluated in vivo demonstrating an improvement in both tumor margin visualization for image-guided radiation therapy and overall survival in tumor bearing mice. Importantly, we found that measurements of contrast enhancement in imaging correlated strongly with tumor response after radiation therapy. Furthermore, we have found that by encapsulating sub–nanometer gold particles within micelles we are able achieve improved excretion profiles compared to larger gold particles, with gold detected in both urine and feces suggesting that particles within this size range are more efficiently removed by the kidneys and liver. Finally, the use of an actively targeted nanoplatform can achieve higher tumor retention, facilitate nanoparticle internalization, and improve tumor specificity. To facilitate the introduction of targeting molecules onto micelle formulations, a naturally occurring surfactant protein oleosin was used to stabilize superparamagnetic iron oxide clusters. Functionalization with targeting ligands (e.g. Her2/neu affibody) was achieved by fusing the biologically relevant motifs to oleosin using standard cloning techniques, and cell specific targeting was confirmed using magnetic relaxation techniques. In the future, we envision that strategies like this will minimize the off–target effects of radiation, reduce tumor burden, provide information on the likelihood of tumor regression in response to therapy and reduce long–term nanoparticle retention.

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