Date of Award

12-16-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Alexandru Biris

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, it is difficult to diagnose, often recurs, has high resistance to chemotherapies, and can be marked by advanced metastatic stages. There is an urgent need to fill the knowledge on nanoparticle penetration, diffusion, and cellular interaction in the context of adaptive PDAC tumor microenvironment to allow the development of new imaging and therapeutic supports. Traditionally, cancer-treating nanoparticles have been engineered and tested on 2D cell cultures, but several studies indicate that this in vitro model does not mimic tumor features closely enough. In contrast, 3D culture models offer more realistic cell–cell and cell–extracellular matrix interactions, they are able to generate cells at various stages (proliferative, quiescent, apoptotic, hypoxic, and necrotic), create gradients of O2, CO2, and nutrients and be co-cultured with multiple types of cells in order to mimic in vivo conditions. In this project, we developed two axes of research to address the need for better PDAC treatments with gold nanoparticles and tumor modeling. First, we developed a complex 3D PDAC spheroid model and used multi-imaging techniques such as fluorescence, photoacoustic, photothermal, and darkfield microscopies as well as surface-enhanced Raman spectroscopy (SERS) to visualize and characterize the interaction of plasmonic gold nanorods. Based on the functionalization of gold nanorods (AR~3) conjugated with an acid sensitive bond to a fluorescence dye, we have highlighted that the fluorescence can be release inside the 3D system after only 2hours of incubation, making it non-suitable to accurately track the nanoparticles within the system. However, we also showed that intrinsic photoacoustic and photothermal properties of the gold nanorods enabling multi-imaging detection even when fluorescence tracking is not possible or ideal. We also developed a new generation of plasmonic gap-enhanced Raman tags (GERTs) that enable enhanced bioimaging in 3D models using SERS and darkfield microscopies. Second, we investigated how the time “aging”, including time of formation and incubation, of the spheroids might influence their phenotype expression. The objective was to determine if these parameters, generally underestimated by the literature, modified the chemotherapeutic answer of free or loaded drug on nanoparticles.

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