First Advisor

Andrea Goforth

Term of Graduation

Summer 2020

Date of Publication

8-3-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Language

English

Subjects

Radiotherapy, Bismuth -- Synthesis, Calcium fluoride -- Synthesis, Radiographic contrast media, Nanostructured materials, Radiation -- Dosage

DOI

10.15760/etd.7421

Physical Description

1 online resource (xiv, 112 pages)

Abstract

Radiation Therapy (RT) is a common treatment for cancerous lesions that acts by ionizing matter in the affected tissue, causing cell death. The disadvantage of RT is that it is most often delivered via an external beam of radiation which must pass through healthy tissues to reach the target site, ionizing matter within healthy tissues as well. To address this drawback, techniques are being developed for increasing RT-induced cell death in a target tissue while minimizing cell death in surrounding tissues. This effect is known as radiation dose enhancement or RT enhancement.

The approach to RT enhancement studied in this thesis involves the use of inorganic nanoparticles (NPs) within target cells. These NPs attenuate X-ray radiation more effectively than the tissues around them, thus depositing more energy into the target tissue. This enhanced energy deposition in the target tissue allows a lesser dose of radiation to be applied to effectively treat the target tissue, which may reduce the risk of cell damage in the surrounding healthy tissues.

In this thesis, the synthesis of two types of RT-enhancing NPs was studied, and preliminary biological assays were used to assess their effectiveness in vitro.

First, a novel synthesis of bismuth nanoparticles (Bi NPs) was developed. Bi NPs are promising RT enhancers due to their high density and atomic number, properties that increase X-ray attenuation. However, syntheses of Bi NPs necessitate air-free technique and specialized equipment. The presented synthesis is aerobic and only uses standard laboratory equipment, providing a practical synthesis that produces Bi NPs of an appropriate size for RT enhancement applications. This is possible due to the formation of an iodobismuthate precursor which is rapidly reduced to form metallic bismuth, eliminating the need for air and light-sensitive bismuth precursors. A survey of the parameters of the reaction has illustrated the impact of various factors to guide further optimization or reproduction of the synthesis. After synthesizing Bi NPs, they were then covered in a silica shell which enabled their further modification in aqueous media.

Second, CaF2:Ln NPs were synthesized and incorporated into an RT enhancing NP which was also radioluminescent (RL). Along with RT enhancement via X-ray scattering, these NPs may enable RL imaging and deep-tissue photodynamic therapy. This work includes a rarely found time point study which elucidates the mechanism by which annealing at high pressure corrects crystalline defects improves their luminescence intensity. The CaF2 NPs were then coated in a mesoporous silica shell which allowed for further surface modification as well as small molecule loading. This shell was then further modified with polyethylene glycol, rendering the NP highly stable in water and lessening the chance of immune response.

Lastly, with both NP types completely synthesized, a variety of biological assays were performed to assess their effectiveness in RT enhancement. Fluorescent probes were used to determine that the presence of NPs increases the number of reactive oxygen species formed during RT, which can be correlated to cell death. In vitro experiments were performed with variable doses of NPs and X-ray radiation to assess the NPs effectiveness at enhancing RT. Finally, an in vivo experiment is reported which supported that the Bi NPs are biodegradable when injected intravenously. These biological assays presented evidence of RT enhancement for both types of NPs in this thesis and directed future work to address some shortcomings in cytocompatibility and reactive oxygen species generation.

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Persistent Identifier

https://archives.pdx.edu/ds/psu/33656

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