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Date of Award

9-2012

Document Type

Campus Access

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemical Engineering

First Advisor

Neil S. Forbes

Second Advisor

Susan C. Roberts

Third Advisor

Joseph Jerry

Subject Categories

Biomedical Engineering and Bioengineering | Chemical Engineering

Abstract

Most chemotherapeutics fail to treat solid tumors because they cannot reach beyond regions proximal to blood vessels and are ineffective against quiescent tumor cells. Motile Salmonella typhimurium , being able to penetrate tumor tissue and chemotax towards distant tumor regions, provides an attractive drug delivery system that could break these therapeutic barriers. This dissertation focuses on two studies using genetic engineering and treatment supplement to upgrade Salmonella tumor-targeting for better therapeutic efficacy.

It has previously been shown in tumor cylindroids that Salmonella lacking ribose chemoreceptors (Trg) primarily localized in tumor quiescence. To evaluate this tumor targeting specificity in vivo , a Trg-deficient Salmonella was created from the attenuated strain VNP20009 by deleting its trg gene. Both VNP20009 trg- and VNP20009 were intravenously administered into the 4T1 murine tumor model. At 12 hours, VNP20009 trg - formed twice as many colonies in quiescent tumor regions as VNP20009, with average colony size 60% bigger. It showed improved abilities to target tumor quiescence and penetrate tumor tissue. Evidence suggests that individualSalmonella bacteria may alternatively penetrate tumor tissue, proliferate or stay dormant. These findings have enriched the understanding of Salmonella tumor targeting, and suggest that controlling the origin of Salmonellaintratumoral behavioral heterogeneity will benefit the quality and reliability of bacterial anticancer therapy.

VNP20009 has been shown to be safe in humans, but accumulates at considerably lower densities in tumors than wild-type Salmonella . Recently it was observed that this may be associated with its inability to synthesize functional lipid A, a pro-inflammatory molecule critical to wild-type Salmonella tumor-invasion. To compensate it, three doses of diphosphoryl lipid A were injected with VNP20009 into the 4T1 murine tumor model. The dose of 2μg lipid A per mouse has raised bacterial count by 4 fold and reduced VNP20009's tumor-targeting variability by 50%. Mathematical simulation of a bacterially produced anticancer peptide diffusing out of VNP20009 colonies was created to give intratumoral peptide concentration and tumor cell killing predictions. Results suggest that injecting VNP20009 with lipid A will enable safe and robust delivery of anticancer agents otherwise unattainable with the bacteria alone.

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