Date of Award

5-2020

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering and Biotechnology (BMEBT)

First Advisor

Kimberly Hamad-Schifferli

Second Advisor

Alexey Veraksa

Third Advisor

Jill A. Macoska

Abstract

Gold nanoparticles have gained interest as theranostic platforms because their surface can be easily functionalized with biomolecules for drug delivery, gene therapy and antigen detection. However, combining nanoparticles with biological environments faces many challenges. When exposed to biological fluids, proteins and other macromolecules adsorb at the nanoparticle surface forming a protein multilayer known as protein corona. As a result, these interface modifications often involve nanoparticle aggregation, protein denaturation, steric hindrance and biomolecule orientation issues, which impair function and decrease overall performance of the NP-biomolecule conjugate. In this Thesis, I studied and engineered the protein corona for (1) therapeutic and (2) diagnostics applications.

The protein corona dictates the behavior of nanoparticles by driving cell uptake, biodistribution and immunological response. In this Thesis, I studied the nanobiointerface to identify a subset of proteins that render high drug delivery and gene therapy efficacy. I formed bio-coronas with the selected proteins and engineered carriers with improved performance in vitro for the drug delivery vectors. Furthermore, I used the protein corona to sequester antigens for biodegradable nanoparticle-based vaccines. I then explored the ability of the vaccine to trigger immunogenicity of the Red-spotted Newt against the deadly fungi Batrachochytrium salamandrivorans.

In diagnostic applications, antibody-based protein biocoronas around gold NPs can be used to render better antigen capture efficiencies. This pre-formed biocorona prevents epitope-binding sites from being masked when introduced in biological fluids. Also, protein coronas that contain certain biological fluids, such as human serum, improve the specificity of point of care immunoassays by preventing non-specific adsorption on nitrocellulose membranes. In this thesis, I used both strategies to optimize the performance of nanoparticle-antibody probes in paper-based immunoassays to detect the foodborne pathogen Vibrio parahaemolyticus in oyster hemolymphs. Also, I broadened the detection capabilities of the nanoparticle-antibody conjugates by tuning the epitope-binding site exposure of polyclonal antibodies with pre-formed protein coronas around two colored gold NPs. This approach provided an accurate assay that distinguishes closely-related antigens by using nanoparticle color patterns.

The exploitation of the protein corona explored in this thesis illustrates novel strategies to improve the performance of nanocarriers for both therapeutic and diagnostic purposes.

Comments

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