Date of Award

12-31-2021

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Green Chemistry

First Advisor

Michelle Foster

Second Advisor

Jason J. Evans

Third Advisor

Marianna Török

Abstract

This thesis consists of two different parts. The first part is devoted to the investigation of the physical properties of amyloid fibrils. Amyloid fibrils, formed through the aggregation of misfolded proteins, are associated with several degenerative human diseases such as Alzheimer’s and Parkinson’s. Additionally, amyloid fibrils have recently received much attention as advanced bio-nanomaterials for interesting applications in material science, nanotechnology, and biomedicine due to their intrinsic properties such as high aspect ratio, small diameter, consistent length, organized structure, and high mechanical strength. Many of these amyloid fibrils are commonly prepared by using harsh acidic methods. Hen-Egg White Lysozyme (HEWL), a low-cost and widely recognized model protein is used to help understand the physicochemical properties of amyloid fibrillogenesis. In the first part of the dissertation, the HEWL protein fibrils are prepared under both traditional, acidic conditions and, as a greener method, neutral conditions. The growth of lysozyme amyloid fibrils, under both acidic and neutral conditions, is monitored over a month-long period using Fluorescence Spectroscopy and Atomic Force Microscopy (AFM). Through AFM images, average morphological and nano-mechanical properties of mature fibrils grown under neutral conditions are shown to be qualitatively very similar to those obtained from fibrils grown under acidic conditions; thus, supporting the aim of the study, which is to create easy, inexpensive, strong, and highly ordered amyloid fibrils with a greener method to use as a natural nanomaterial. The described methodology was further developed into a laboratory experiment for undergraduate students in biochemistry, chemistry, and physical chemistry, helping them learn modern spectroscopic techniques that are essential tools to visualize materials at nanoscale level as early as possible. This three-week laboratory helps students understand the operation of AFM, the visualization of structural changes of protein, as well as the spectroscopic analysis of heat-denatured and amyloid-type aggregates associated with neurodegenerative diseases.

The second part of the thesis describes the development of a new liquid metal nanoplatform-based photosensitizer drug delivery strategy that leverages the tumor microenvironment to achieve a photodynamic therapeutic treatment of pancreatic cancer. Developing a cancer theranostic nanoplatform to effectively diagnose and cure tumors while reducing the potential side effects of traditional chemotherapy is of great significance. Herein, we use the eutectic alloy of gallium and indium (EGaIn, 75% Ga, 25% In), which is a liquid metal at room temperature, and when exposed to air it forms a thin (~0.7 nm) passivating oxide layer. EGaIn nanoparticles have a chemically and mechanically stabilizing gallium oxide (Ga2O3) skin on their surface. Eutectic Gallium Indium (EGaIn) nanoparticles were successfully conjugated with a water-soluble cancer targeting ligand, Hyaluronic acid (HA), and a photosensitizer, Benzoporphyrin derivatives (BPD) via a simple green sonication method. BPD also attaches to the oxide layer, thus by using photodynamic therapy the BPD can be activated and it can destroy the cancer cells using radical chemistry. The prepared sphere shaped EGaIn nanoparticles, with a core–shell structure, presented high biocompatibility and stability. The results from phototoxicity evaluation of EGaPs nanoparticles show that near infrared (NIR) laser stimulated EGaPs have great potential to be used in effectively eliminating cancer cells due to their single oxygen generation and make a promising vehicle for photodynamic therapy. The final stage of this dissertation is to adapt the EGaIn nanoplatform that is described above to be used with a different targeting ligand, Folic acid (FA), for the treatment of breast cancer. Therefore, a new EGaIn nanoplatform (EFB) is developed with Folic Acid (FA) and a BPD photosensitizer by coating the passivating oxide layer. The physiochemical properties of the newly developed EFB nanoplatform are explored by using AFM, SEM DLS and Fluorescence spectroscopy. In addition, the EFB nanoparticles are further analyzed to evaluate their cytotoxicity in vitro on breast cancer cell lines. Results show that EFB nanoparticles are also non-toxic biodegradable nanoplatforms that can be potentially used to treat breast cancer.

Comments

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