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Chemical Engineers Publish Cover Story in Journal of Controlled Release

Neil Forbes

Chemical Engineering (ChE) graduate student Miaomin Zhang and his advisor ChE Professor Neil S. Forbes recently published the cover article of the Journal of Controlled Release (vol 199, February 10th), which has an impact factor of 7.8. The title of the article is "Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating."

For more than 12 years, the Forbes research team has been working on non-pathogenic Salmonella bacteria that can use their own self-propulsion system to venture deep into tumors and deliver cancer-destroying agents, all without causing the vicious side effects of many chemotherapy treatments. Forbes recently received a five-year, $1.56-million grant from the National Institutes of Health to engineer what he calls “super-safe Salmonella bacteria” to act as Trojan Horses and deliver cancer-killing agents directly into tumors. His Salmonella vectors are designed to steal into cancer tumors, interrupt essential cell processes there, destroy cancer cells, eliminate cancer stems cells, reduce tumor volume, and block the formation of metastases.

The article in the Journal of Controlled Release describes part of that overall research. As the abstract of the article explained, “Chemotherapeutics fail to effectively treat tumors because they cannot reach quiescent regions far from blood vessels. Motile Salmonella are an attractive delivery system that could break this therapeutic barrier. However, little is known about the dissemination and tissue penetration of individual bacteria in tumors after intravenous administration. We hypothesized that eliminating the Trg receptor [a sugar receptor in Salmonella] would improve accumulation in tumor quiescence.”

To test this hypothesis, the UMass researchers deleted the trg gene from nonpathogenic Salmonella. To quantify individual bacterial behavior, they measured tissue penetration in a tumor-on-a-chip device created in their lab and measured colony localization in mouse tumors using immunofluorescence. In tumors in vitro and in mice, trg-deficient Salmonella penetrated farther into tissue than control bacteria. This difference in localization was caused by the inability to sense sugars in well perfused tissue.

The abstract added that “In addition, colonization was most pronounced in poorly vascularized tumor regions. We show that deletion of trg amplifies Salmonella accumulation in quiescent tumor regions, and, for the first time, identify biological processes that control bacterial distribution in tumors. Understanding how Salmonella penetrate tissue, target quiescence, and specifically replicate in tumors are essential steps toward creating a tightly controlled, tunable bacterial therapy.”

The article by Zhang and Forbes in the Journal of Controlled Release was also accompanied by an essay written by Kinam Park of the Purdue University Departments of Biomedical Engineering and Pharmaceutics that describes the significance of their research.

Park explained that “Zhang and Forbes quantified mechanisms of bacterial migration in tumors that, to date, have been largely unexplored. They show that the bacterial sugar receptor, Trg, plays a critical role controlling where Salmonella accumulate in tumors. They did this by deleting the trg gene from the genome of nonpathogenic Salmonella and then measuring the behavior of individual bacterial in a tumor-on-a-chip device and in mouse tumor models. They found that deleting the Trg chemoreceptor amplified accumulation in therapeutically resistant quiescent regions.”

Zhang and Forbes also showed that bacteria have three distinct “lifestyles” in tumors that control colonization. They observed that bacteria are either penetrating, proliferating, or inactive.

As Park concluded, “Understanding how Salmonella penetrate and target quiescence is an essential step toward creating a tightly controlled, tunable bacterial therapy. The results presented by Zhang and Forbes will open the door to new avenues of research, and will encourage more exploration into the use of bacteria as delivery agents.” (February 2015)

 
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