Synchronized cycles of bacterial lysis for in vivo delivery

Abstract

The pervasive view of bacteria as strictly pathogenic has given way to an appreciation of the widespread prevalence of beneficial microbes within the human body1–3. 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 therapies4–6. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ7–10. 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 delivery 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 therapies11, 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.

Dual Functionality nanobioconjugates: a New Tool for Intracellular Bacterial Targeting in Cancer cells?

“…They utilize the natural colonizing properties of bacteria and viruses to deliver drug to the diseased sites. A 2016 study by Din et al showed how a clinically relevant bacterium could be engineered using tools of synthetic biology to lyse synchronously at a threshold population density and release genetically encoded anticancer cargo on demand in the required vicinity [26]. Although, natural carriers like bacteria and viruses are superior over synthetic analogs due to their inherent colonizing tendency into tumor cells, combating their immune response inside the body poses a big challenge.…”

Vaccine Allied Biologics

“…Others ,however ,own such potentials after getting modification in their genetic constitutions. Two examples of genetically modified bacteria to be active as cancer killer bacteria and are being briefed [15,16] in the followings; 1-Synchronizing bacterial lysing strains that have the ability of an in-vivo delivery system that grow and release cytotoxic agents insitue which acts as circuit engineered bacteria [15] .…”

Bacteria synchronized for drug delivery

“…Now, Din et al 1 exploit a relationship between bacteria and diseased human tissue for a therapeutic purpose. On page 81, the authors outline a system in which engineered bacteria acting as drug-delivery vehicles simultaneously break down, releasing an antitumour drug in synchronized cycles to maximize delivery efficiency and minimize toxicity.…”

“…Despite these features, bacteria alone (whether engineered or not), are unlikely to eradicate tumours 1,5 . In the current study, treatment of mice with the engineered microbes in combination with chemotherapy did not destroy the tumour; instead tumours shrank for 18 days, after which regrowth occurred.…”

“…One challenge to using periodically lysing bacteria to treat non-cancerous diseases that require long-term treatment is that the bacterial-degradation by-products released in each lysis cycle might be absorbed into the blood and build up, causing toxic systemic effects. Choosing less-toxic bacterial strains or creating attenuated strains (for example, by deleting the msbB gene, which is involved in making endotoxin 8 1 constructed a genetic circuit in tumour-targeting bacteria that mediates drug production and release through cell lysis in synchronized, repeated cycles. a, Binding of the signalling molecule AHL to its receptor protein LuxR leads to their subsequent interaction with, and activation of, the promoter DNA sequence P luxI .…”