Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Amber Doiron

Abstract

Nanotechnology holds great promise in biomedicine towards new diagnostics, new therapies, and improved patient outcomes. This work explores both the application of a novel nanoparticle in an established field of cancer treatment as well as an investigation of the human health implications of nanoparticles in intravenous applications. First, novel dye-linked zinc oxide nanoparticles (NPs) were investigated for use as photosensitizers (PS) for photodynamic therapy (PDT) due to their excellent thermal- and photo-stability. To overcome the limitations of current cancer treatments, we investigated the effectiveness of ZnO-Dye 847 NPs as a near infrared (NIR) PS in PDT. The NPs were surface modified with poly (ethylene glycol) (PEG) to increase particle biocompatibility and reduce aggregation. The particles produced reactive oxygen species (ROS) upon NIR irradiation in a concentration- and time-dependent manner; the in vitro level of ROS in cancerous cell line MCF-7 was higher than in human endothelial cells. The quantum yield (η) of the new NPs was found to be 40% higher than the current clinically used PS. Due to limited toxicity when coated with PEG, the ability to produce ROS upon NIR irradiation, preferential cytotoxicity, and high η using a NIR lamp with low power density, these novel Dye 847- ZnO NPS hold promise to act as photosensitizers for biomedical applications in PDT.Understanding the potential impact of NPs on human health is a pressing concern due to the promise that these technologies hold in improving diagnosis and therapy. For particles administered intravenously or particles that eventually reach the bloodstream, the endothelial barrier between the blood flow and all other tissues of the body is a key point of interaction. Particles of approximately 20 nm have been identified to induce a mechanism that increases paracellular permeability upon exposure of EC to NPs, known as nanomaterial-induced endothelial leakiness (nanoEL). Our previous studies indicated that calcium (Ca2+) is key in regulating the nanoEL effect, and we hypothesized that exposure to 20 nm NPs leads to activation of a specific Ca2+ ion channel, leading to increased understanding of the mechanism of nanoEL. On addition of antagonist to transient receptor potential vanilloid- type 4 (TRPV4), the intracellular Ca2+ dropped more than 9 times compared to untreated control, indicating the activation of TRPV4 channel upon exposure to 20 nm NPs. This result coupled with our previous work indicated that 20 nm NPs induced nanoEL by activation of the TRPV4 channel in human umbilical vein endothelial cells (HUVEC). Moreover, similar results were achieved with human coronary artery endothelial cells (HCAEC) and human cardiac microvascular endothelial cells (HMVEC-C), deepening our understanding of the size-specific nanoEL effect of 20 nm NPs on Ca2+ internalization. This is a significant finding towards the development of nanoparticle technologies.

Language

en

Number of Pages

240 p.

Available for download on Tuesday, September 19, 2023

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