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Author ORCID Identifier

https://orcid.org/0000-0001-6212-7769

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2021

Month Degree Awarded

May

First Advisor

Vincent M. Rotello

Subject Categories

Cancer Biology | Immunotherapy

Abstract

Cell surface harbors rich information regarding the status of cell health. Being able to monitor and detect its changes in response to stimuli will provide crucial information in drug discovery, disease diagnosis, and human health. Despite the efforts and breakthroughs made possible through the specific sensing approach, there are significant challenges in extracting the information on the cell surface in a quantitative and reliable way. To address this challenge, I took the approach of array-based, hypothesis-free sensing in which the engineered sensors selectively interact with target analytes, producing a distinct pattern of response that enables analyte identification. This signature-based pattern recognition is particularly powerful in identifying the subtle changes on complex analytes (e.g. cell surfaces), rather than identifying specific elements within them. In this dissertation, I have applied such sensing strategy to facilitate the drug discovery process with the goal of rapidly identifying potential therapeutic candidates. Specifically, I utilize nanomaterials and polymers to construct effective nanosensors to phenotype mammalian cells. The first part of the thesis focuses on sensing a key target in cancer: cancer stem cells (CSCs). Utilizing a supramolecular nanoparticle-fluorescent protein sensor array, we successfully discriminated breast CSCs from non-CSCs, as well CSCs that had differentiated in vitro. Furthermore, we integrated array-based sensing with nanoparticle surface engineering to screen and identify a candidate nanoparticle that not only induces CSC differentiation but also renders them more susceptible to drug treatment. The second part of the thesis demonstrates the power of array-based sensing in immunotherapies with the example of profiling different macrophage polarization states. I developed a novel sensor system that employs only two sensor elements to generate a high data density of five channels. Such high-content information enabled us to quantitatively discriminate among major macrophage polarization states as well as multiple less-characterized phenotypes in a matter of minutes. Overall, array-based sensing provides a simple and robust tool for cell phenotyping and holds promises for addressing challenging questions in biomedicine.

DOI

https://doi.org/10.7275/21780032.0

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