Germs under cover
Bacterial Invisibility Cloak Developed for Cancer Treatment
Daniil Sukhinov, Naked Science
The use of bacteria for therapy is a new, alternative and largely controversial approach to the treatment of a wide range of cancers. One of the most obvious problems of this method of treatment is the toxicity of delivery bacteria to the human body. Unlike many traditional methods of targeted drug delivery, bacteria continue to live and multiply in the patient's body.
The human immune system recognizes bacteria as foreign and dangerous, which causes an inflammatory reaction. This problem is solved either by genetic engineering of bacteria to clean the surface of microorganisms from antigens that the immune system reacts to, or by coating the surface of living drug deliverers in special molecular protection.
The first method weakens the bacteria: they reproduce poorly and die quickly, without delivering the medicine. The second one is able to give microorganisms too much time to reproduce, which will lead to uncontrolled growth and because of which a strong inflammatory reaction may begin.
Therefore, in a new study, the results of which are published in the journal Nature Biotechnology (Harimoto et al., A programmable encapsulation system improves delivery of therapeutic bacteria in mice), American biotechnologists focused on genetic engineering and controlled biosynthesis of molecular defense in Escherichia coli Nissle 1917 bacteria. They used a capsular polysaccharide synthesized by the bacteria themselves (capsular polysaccharide, CAP), covering their surface and protecting them from detection by the human immune system, and found a way to control its production.
Schemes of programmable encapsulation of E.coli bacteria (a) and conducting experiments on the treatment of cancer in mice with various types of E.coli (b and c). In addition, changes in antitumor toxicity and survival of various types of bacteria are shown. Gray ovals – bacteria without SAR protection, black – with permanent SAR protection, blue – with programmable SAR protection. Drawings from the article by Harimoto et al.
"We hacked the CAP system of the probiotic strain of E.coli Nissle 1917," explains Tetsuhiro Harimoto, a graduate student in the Department of Biomedical Engineering at Columbia University (USA) and co—author of the study. — With CAP, these bacteria can temporarily evade an immune attack; without CAP, they lose their protection and can be excreted from the body. So we decided to try to create an effective switch."
To do this, the researchers developed the iCAP (inducible CAP) system. They control the iCAP system using an external signal — a small molecule called IPTG (isopropyl-b-D-thiogalactopyranoside). In the presence of IPTG, the bacterium synthesizes CAP and creates an invisibility cloak that hides it from the immune system. If this molecule is removed, then within six hours the protective cover from the bacteria will completely fall off.
"What's really interesting about our work is that we can dynamically control the system," comments Tal Danino, associate professor of biomedical Engineering at Columbia University and one of the research supervisors. — We are able to regulate the time during which bacteria survive in human blood and increase the maximum tolerated dose of bacteria. We have also shown that our system opens up a new bacterial delivery strategy in which it is possible to inject bacteria into one known tumor and cause them to migrate in a controlled manner to distant tumors, such as metastases — cancer cells that spread to other parts of the body."
Demonstration of the programmability of the E.coli bacterial protection CAP depending on the concentration of the IPTG molecule (b and c).
The effectiveness of the iCAP system was tested on mice with cancer. The researchers added the ability to produce antitumor toxin to E.coli with the iCAP system and were able to reduce tumor growth in models of intestinal cancer and breast cancer in rodents. Moreover, the results for E.coli with the iCAP system were significantly better than without it.
The team also demonstrated controlled migration of bacteria in the body to tumor metastases. They injected E.coli with the iCAP system into one tumor, gave mice water containing IPTG, which activated CAP protection. After that, iCAP E.coli were observed to exit the original tumor and migrate to non-injected tumors.
In the future, the authors plan to improve their technology using other organisms, types of molecular coverings (like CAP) and control systems with the possibility of autonomous operation of the surface properties of therapeutic bacteria. In addition, one of the main and most difficult future tasks is clinical trials of the system on a person who is more sensitive to bacterial endotoxins in comparison with mice.
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