Date of Award:

5-2018

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biological and Irrigation Engineering

Advisor/Chair:

David W. Britt

Co-Advisor/Chair:

Jixun Zhan

Third Advisor:

Anhong Zhou

Abstract

This research focused on development of nanoparticle- based therapeutics against amyloid fibrils. Amyloid fibrils are associated with various diseases such as Parkinson’s, Huntington’s, mad cow disease, Alzheimer’s, and cataracts. Amyloid fibrils develop when proteins change their shape from a native form to a pathogenic “misfolded” form. The misfolded proteins have the ability to recruit more native proteins into the pathogenic forms, which self-assemble into amyloid fibrils that are hallmarks of the various protein-misfolding diseases listed above. Amyloid fibrils are highly resistant to degradation, which may contribute to the symptoms of amyloid diseases. Synthetic drugs, natural compounds, and antibodies are widely explored for potential to stop pathogenic protein assembly or to promote fibril degradation and clearance, but to date have had little success in relieving symptoms in clinical trials. In this research, I have synthesized fluorine-containing silica nanoparticles (NPs), and tested their fibril-inhibiting activity against amyloid fibrils formed by a non-pathogenic protein, β-lactoglobulin (BLG). These fluoro-silica NPs prevented BLG amyloid formation, whereas non-fluorinated nanoparticle analogs did not inhibit fibrillation under the same reaction conditions. The fluoro-silica NPs interacted with the BLG protein in a manner that prevented the protein from adopting a form that could self-assemble into fibrils. Additional applications of the NPs were explored as small-molecule drug-delivery systems; such that multiple functionalities could be introduced into a single nano- therapeutic.

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