Author ORCID Identifier

https://orcid.org/

0000-0002-6839-5729

Date of Graduation

5-2022

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Sunil Krishnan

Committee Member

Sang Hyun Cho

Committee Member

Wendy Woodward

Committee Member

Lon Wilson

Committee Member

William Plunkett

Abstract

This thesis presents development and evaluation of the potential of three new nanoparticles for biomedical applications. With the rapid growth of the field of nanoscience, researchers have explored developing nanoparticles for various biomedical applications, including imaging, therapy, and drug delivery. This thesis demonstrates the development of two C­60 fullerene based nanoparticles and one boron based nanoparticle to answer key questions related to their biological potential.

In the first part of the thesis, we describe synthesis and characterization of a pure boron nanoparticle containing asolectin phospholipid-based liposome construct prepared using a water-in-oil emulsion method, as a novel alternative agent for boron neutron capture therapy (BNCT). A tumor-specific targeting ligand, folic acid (FA), was conjugated to polyethylene glycol to produce a folate-functionalized liposome for improved targeted delivery and accumulation of boron in cancer cells. Cellular uptake monitored by fluorescence microscopy confirmed the targeting capability of FA-conjugated liposomes. Accumulation of FA-conjugated liposomes in C6-brain tumor cells was much higher than that of non-FA conjugated liposomes under the same conditions. ICP-MS (Inductively Coupled Plasma Mass Spectrometry) quantification confirmed that boron accumulated in cancer cells to sufficient intracellular concentration for therapeutic benefit from BNCT. These liposomes show blood-brain barrier (BBB) crossing ability, low cytotoxicity, and excellent stability under physiological conditions. Thus, these liposomes are a promising new boron carrier for BNCT. Collectively, these studies suggest that liposomes encapsulated with boron-enriched components and decorated with PEG-FA represent a promising approach to the creation of novel boron carriers for cancer BNCT.

In the second part of the thesis, we describe the development of a C60 fullerene construct decorated with two Gd ions (Gd2C60) for BNCT and magnetic resonance imaging (MRI) showing exceptional water solubility and transport across cellular and physiological barriers. We demonstrated our compound to have significantly improved relaxivity by designing our particle to be small and relatively spherical, allowing Gd to have great water exchange rates. We also explored its potential to be used as a radiosensitizer for photon radiation; however, even though we were able to achieve sufficient amount of Gd within cells to generate enhanced secondary electron showers from Gd, a high atomic number material, the resulting oxygen free radicals were most likely scavenged by the fullerene backbone, dampening the radiosensitization effect.

In the final part of this thesis, we take the backbone of our previously designed molecule, a biocompatible C60 fullerene, and derivatize it with serinol only to make it both extremely water soluble and highly efficient at free radical scavenging. We developed a customized method to derivatize C60 fullerene with serinol to make it amphiphilic in nature, and demonstrated how C60­-ser can protect epithelial, mesenchymal, endothelial and neuronal cells from proton and photon radiation damage via reduction of oxidative stress, metabolic reprogramming, reduction of DNA damage, and improvement in clonogenic survival. We also demonstrated its ability to improve survival following whole body irradiation but not tumor protection. Though more in vivo experiments with various tumor types need to be performed to show significance, initial results look very promising. We anticipate that this common thread of C60-ser protecting cells against oxidative stress that contributes to normal tissue radiation injury in multiple and organ systems may make C60-ser a turnkey class solution for protecting against radiation injury associated with irradiation of tumors in most locations.

Keywords

nanoparticles, radiation therapy, boron nanoparticles, fullerene, radioprotection

Available for download on Thursday, April 27, 2023

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