Date of Award

12-31-2018

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering and Biotechnology (BMEBT)

First Advisor

Jonathan Celli

Second Advisor

Chandra Yelleswarapu

Third Advisor

Changmeng Cai

Abstract

Advances in the development of nanoparticle-based platforms in medicine have shown promise for a wide range of applications of these platforms in cancer imaging and therapeutics. In particular, gold nanoparticles (GNP) exhibit exceptional versatility in their ability to interact with varying frequencies of electromagnetic radiation in ways that can be leveraged to impart or enhance cytotoxic responses or to generate image contrast. In light of other works pointing to the promise of GNP for radiosensitization, this study uses a 3D cell culture approach to study the impact of GNP uptake and localization on radiation dose enhancement, as well as on combined photodynamic/photothermal treatment. The use of 3D cell cultures reveals that GNP resides in the extracellular matrix (ECM) for surprisingly long durations (several days) after initial delivery and prior to localization in tumor nodules, an effect which, as it will be shown here, has a big impact on the treatment outcomes for nanoparticle-aided therapy.

Here we show that heavy metal such as gold in a form of gold nanorods (GNRs) influences photodynamic therapy (PDT) outcome. GNRs were used to excite surface plasmon resonance (SPR) and consequently, to induce heat via photo-thermal treatment (PTT), which combined with PDT raises treatment response. It turned out that presence of GNRs does enhance PDT outcome, not via thermal effect, but rather because of gold photochemistry and the appearance of the heavy atom effect. To achieve this effect, the presence of GNRs in the vicinity of the photosensitizer which accumulates in tumor nodule is necessary. Therefore, the treatment outcome of this combined light-based therapy will certainly depend on the amount of GNRs present in the 3D cancer nodule itself.

In combined x-ray/GNP treatment, GNPs act as a source of short-range secondary radiation effects where, again, disproportionate accumulation of GNP in ECM significantly reduces radiation response in 3D tumor spheroids.

In addition to pointing to the importance of using a suitable model system that restores ECM interactions, this insight suggests that timing of the PDT/PTT combination or radiotherapy following administration of gold nanoparticles is a significant factor in determining treatment outcomes for nanoparticle-aided therapy.

Comments

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