Dissertations, Theses, and Capstone Projects

Date of Degree

6-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Stephen O'Brien

Advisor

Rein Ulijn

Committee Members

Brian Zeglis

Jason Lewis

Abstract

Nanotechnology holds great potential for preventing and combating life-threatening diseases, as evidenced by the success of the lipid nanoparticle (LNP)-based mRNA vaccines amid the COVID-19 global pandemic. Research and development of cancer nanotherapeutics has been progressing at an exponential rate in the past decades. Advantages of using nanomedicine for cancer treatment versus conventional chemotherapeutic drugs include enhanced drug accumulation in the tumor and extended blood circulation. In addition, nanomaterials are also developed for cancer imaging and diagnostics. Since the past decade, the combination of therapy and diagnosis, or theranostics, has become a focus in cancer research. This thesis provides novel strategies to develop surface-functionalized nanomaterials for cancer theranostics. In one project reported herein, surface-modified barium titanate (BaTiO3, or BT) nanoparticles (NPs) were developed as novel biocompatible computed tomography (CT) contrast agents. Three approaches for the surface modification of 8 nm BT NPs were developed and compared in terms of aqueous dispersibility, size, cytotoxicity, and ultimately feasibility as CT contrast agents for cancer imaging. The results demonstrated the possibility to passively target tumors by modifying the surface of nanomaterials.

In a second project, a self-assembling NP system using enzyme-responsive peptides is reported. Novel peptides were designed and immobilized on gold NPs (AuNPs) to target cancer-specific enzymes, matrix metalloprotease-9 (MMP-9). The assembly of gold NPs (AuNPs) was achieved by enzymatic unveiling of the surface-bound zwitterionic peptides that drove electrostatic interactions of the NPs. The increase in size after NP assembly resulted in size-induced selection of cellular uptake and subsequent cell toxicity. Control studies using non-enzyme-responsive peptides, hence non-assembled NPs, showed no effects on cancer cells. This project demonstrated the use of self-assembly NPs for drug-free cancer therapy through an active targeting strategy.

In the last project, the use of non-covalent fluorescent labeling for STED based super-solution imaging of self-assembling peptide-functionalized AuNPs is reported. The fluorescent labeling was achieved by electrostatic binding of anionic sulfonates of Alexa-488 dye to the cationic side chains on the peptides. With further optimization on minimizing the fluorescence quenching, this approach has the potential to image nanostructures smaller than the diffraction limit known to conventional confocal microscopy. This simple and universal strategy could be used to study bio-inspired active assembly and could have applications in biomedical research, including in vivo imaging and the investigation of biochemical processes using nanosized or supramolecular materials. Overall, the use of self-assembled NPs has great potential in enhancing the imaging capabilities of confocal microscopy and could lead to new applications in various fields.

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