Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

David P. Cormode

Abstract

Early detection by X-ray mammography allows for timely treatment of breast cancer, thus preventing disease progression and improving patient outcome. However, the sensitivity of mammography is reduced in women with dense breasts, which may lead to delayed diagnosis, more advanced stage upon detection, and reduced survival. Thus, a dual energy technique has been implemented to improve the diagnostic sensitivity of mammography. Dual energy mammography (DEM) employs k-edge imaging to separate iodine contrast materials and distinguish iodinated tumors from surrounding tissue. However, iodine agents have drawbacks such as potential adverse reactions and low contrast generation for DEM. Recently, silver has been identified as an element that has superior DEM contrast properties. In this thesis, we present the development of silver sulfide nanoparticles (Ag2S-NP) as a low-cost, biocompatible contrast agent specialized for DEM. Hydrophobic Ag2S-NP were encapsulated in phospholipid micelles with iron oxide nanoparticles and a near-infrared fluorophore to create a multimodality nanoprobe. This agent showed negligible cytotoxicity and allowed breast tumors to be detected in vivo with DEM and other imaging methods, thus providing a safe and flexible screening option. To increase the likelihood of translation, sub-5 nm, hydrophilic Ag2S-NP were formulated to be renally-clearable with 85% of the injected dose being excreted within 24 hours of intravenous injection. This is amongst the best clearance of similarly sized nanoparticles reported thus far. To further improve the clearance efficiency, we employed a novel microfluidics approach to synthesize Ag2S-NP under ambient conditions and to maintain the integrity of surface ligands. Intact coating shell improved the clearance of Ag2S-NP by lowering uptake in the liver and shifting nanoparticle distribution into the hepatocytes. This initial finding highlights the impact of synthetic conditions on ligand integrity and subsequent clearance and nano-bio interactions. Finally, small core Ag2S-NP were loaded in biodegradable polymers to form a multifunctional, theranostic agent, which can be used for multimodality tumor detection, image-guided surgery, and localized tumor ablation via phototherapy. This work expands the list of potential DEM specific contrast agents and represents a significant advancement in the biomedical uses of Ag2S-NP.

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