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Author ORCID Identifier

N/A

Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemical Engineering

Year Degree Awarded

2019

Month Degree Awarded

May

First Advisor

Shelly R. Peyton

Subject Categories

Biochemical and Biomolecular Engineering | Biological Engineering | Biomaterials | Cancer Biology

Abstract

Cancer is a clinically challenging disease to treat because drug resistance often occurs for patients either at the onset of the treatment or after it has been administered over a period of time. To address this problem, there is a significant need for the development of new and more effective treatment options. Currently, the initial stages of drug development rely on the identification of novel small molecules by screening large libraries of compounds on established cell lines grown on two-dimensional tissue culture plastic plates. However, many compounds that appear to be promising at this stage of drug development end up resulting in poor clinical efficacy. I propose that this result is partially due to the fact that in vitro high-throughput screening of small molecules does not account for a multitude of factors that impact how cells will respond to a drug in vivo.

Tumors reside in a complex microenvironment that provides many cues to the cancer cells. Cell-cell and cell-matrix interactions, soluble factors, and non-cancerous cells are components of the tumor microenvironment that could affect how cancer cells respond to drug treatment. Biomaterials have been developed to recapitulate some of these features to study cell behavior in vitro. However, for biomaterials to be truly useful for drug screening, they must be enabled for high-throughput screening technologies. Therefore, I adapted three existing biomaterial platforms to 96-well plates with semi-automated robotics. Since the behavior of cells is dependent on their microenvironment, I then evaluated the applicability of drug response metrics to studies that employ biomaterials. Finally, I used a synthetic 3D hydrogel to study ovarian cancer drug response. For a cell line grown as spheroids and patient-derived spheroids encapsulated in this hydrogel, I observed different drug responses in 3D than cells as a monolayer on tissue culture plastic. Ultimately, the work that I present here will lead to the incorporation of biomaterials in high-throughput drug screening to aid in making preclinical predictions that are more likely to represent clinical responses than screening on tissue culture plastic. This will lead to more effective treatment options and improve clinical outcomes of cancer patients.

DOI

https://doi.org/10.7275/m5z8-yr76

Available for download on Sunday, November 10, 2019

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