Synchronized cycles of bacterial lysis for in vivo delivery
Name
Synchronized cycles of bacterial.pdf
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Author(s)
Din, M. Omar
Prindle, Arthur
Selimkhanov, Jangir
Julio, Ellixis
Tsimring, Lev S.
Hasty, Jeff
Danino, Tal
Skalak, Matthew T.
Allen, Kaitlin N.
Atolia, Eta
Date Issued
August 2016
Journal
Nature
Publisher
Nature Publishing Group
Citation
Din, M. Omar, Tal Danino, Arthur Prindle, Matt Skalak, Jangir Selimkhanov, Kaitlin Allen, Ellixis Julio, et al. “Synchronized Cycles of Bacterial Lysis for in Vivo Delivery.” Nature 536, no. 7614 (July 20, 2016): 81–85.
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Author's final manuscript
Abstract
The pervasive view of bacteria as strictly pathogenic has given way to an ppreciation of the widespread prevalence of beneficial microbes within the human body. Given this milieu, it is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ. Here, we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We use microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug deliver platform via co-culture with human cancer cells in vitro. As a proof of principle, we track the bacterial population dynamics in ectopic syngeneic colorectal tumors in mice. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies, we orally administer the lysis strain, alone or in combination with a clinical chemotherapeutic, to a syngeneic transplantation model of hepatic colorectal metastases. We find that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumor activity along with a marked
survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Department of Mechanical Engineering
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DOI of Published Version
https://doi.org/10.1038/nature18930
