Date of Award

12-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Darin Jones

Second Advisor

Cesar Compadre

Abstract

There is an unmet need for safe and effective radiological countermeasures that can be stockpiled by the United States Government and rapidly deployed to protect populations during radiological emergencies. A major nuclear reactor failure or nuclear attack in large urban areas would result in catastrophic public health consequences. Currently, there are no safe and effective radioprotector or radiomitigator products that offer multi-organ protection and are suitable for stockpiling. One of the most promising alternatives is the vitamin E tocotrienols which have shown remarkable ability to protect the hematopoietic, gastrointestinal, and other systems against radiation, with very low toxicity. Unfortunately, the oral bioavailability of the tocotrienols is limited, necessitating the use of high subcutaneous doses, which limits their applicability as radiomitigators. In this dissertation, we demonstrated the potential of tocoflexol as a radiomitigation agent, which is a tocotrienol analogue our laboratory strategically designed for enhanced bioavailability. Although drug development is a nearly overwhelming task, in this case, we have optimized the chances of success by designing tocoflexol via a rigorous computer-aided drug process based on the following considerations: a) Mechanism-based: Tocoflexol is designed to be transported by the α-Tocopherol Transfer Protein (ATTP). ATTP is the protein responsible for maintaining the plasma concentration of the tocopherols. The reason for the limited bioavailability of the tocotrienols is their limited binding to this transport protein. b) Optimization: The target tocoflexol was selected by a state-of-the-art computer-aided molecular dynamics approach that has allowed us to remove from consideration numerous compounds with limited potential, and to focus on the most promising candidate. c) Safety: To optimize the potential for safety, tocoflexol was designed seeking the smallest possible chemical alteration of the naturally occurring, and very safe, vitamin E constituents. d) Availability: We have developed a synthetic procedure that starts with readily available naturally occurring oils and is suitable for upscaling to produce large quantities of tocoflexol e) Novelty: Tocoflexol represents a novel radiation countermeasure compound, developed by our team, for which we have received patent protection. Tocoflexol have been shown to protects against lethal doses of radiation, has rapid cell uptake, have a favorable pharmacokinetic profile (rapid onset and slow elimination), we propose that tocoflexol will be effective as a radiomitigator. In this work, we synthesized delta (DTF) and gamma tocoflexols (GTF). The radiomitigation efficacy of (DTF) was evaluated in a mouse model by total body irradiation with lethal doses of 9.5 Gy, and then 24 hours after radiation, mice were dosed with 300 mg/kg of DTF via oral and subcutaneous routes. 30-day survival study showed a 30% of irradiated mice treated with DTF survived compared to the mice in the control group which were not given DTF. Toxicity study with a dose of 600 mg/kg shows DTF are not toxic. Molecular dynamics simulation and modeling studies also show that both isomers of DTF and GTF were able to adopt conformations which allow them to bind α-tocopherol transport protein (ATTP). In this study, we showed that tocoflexols have the potential to be developed into a safe and effective radiomitigator that can be stockpiled and rapidly deployed to protect civilians and military personnel during radiological emergencies, which will benefit public health and national security.

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