[Nature sub-issue] Designing a "stealth coat" for bacteria to deliver drugs to tumors and kill cancer cells!

Introduction: Live bacterial therapy has been proposed as an alternative approach to the treatment of various cancers
.

Recent studies have developed a "stealth" system with tunable and dynamically expressed surface capsular polysaccharides for enhanced systemic delivery

Columbia University School of Engineering researchers report they have developed a "stealth" system that temporarily hides therapeutic bacteria from the immune system, allowing them to more efficiently deliver drugs to tumors that kill mice of cancer cells
.

By manipulating the microbe's DNA, they programmed the genetic circuits that control the bacteria's surface, building a molecular "coat" that encases the bacteria

They have developed a "stealth" system that temporarily hides therapeutic bacteria from the immune system, allowing them to more efficiently deliver drugs into tumors, killing cancer cells in mice

We were able to dynamically control this system, which could regulate how long bacteria survive in human blood and increase the maximum tolerated dose of bacteria

"With CAP, these bacteria can temporarily evade immune attack; without CAP, they lose their envelope protection and can be cleared from the body

effective switch

valid switch valid switch

To do this, the researchers modified a new CAP system, which they called iCAP
.

They controlled the iCAP system by giving it an external cue: a small molecule called IPTG, which allows for programmable and dynamic changes on the E.

Treatment with bacteria

Treatment with bacteria Treatment with bacteria

While the use of bacteria for therapy is a new and alternative approach to the treatment of many types of cancer, there are many challenges, especially their toxicity
.

Unlike many traditional medicines, these bacteria are alive and can multiply in the body

Danino's postdoctoral research scientist Jaeseung Hahn, who led the project with Leong's lab, noted, "In clinical trials, these toxicities have proven to be a critical issue, limiting the doses we can give the bacteria and compromising efficacy
.

Some trials had to be terminated due to severe toxicity

ideal bacteria

ideal bacteria ideal bacteria

The ideal bacteria should be able to evade the immune system when entering the body and reach tumors efficiently
.

And once they enter the tumor, they need to be eliminated elsewhere in the body to minimize toxicity

The ideal bacteria should be able to evade the immune system when entering the body and reach tumors efficiently

The research team also demonstrated controllable bacterial migration in vivo
.
Past research has shown that small amounts of bacteria leak out of the tumor as it grows
.
For the new study, the Columbia team used iCAPs to show that they can control the leakage of bacteria from tumors, as well as their translocation to other tumors
.
They injected E.
coli iCAP into one tumor, fed mice water with IPTG, activated iCAP within one tumor, and saw E.
coli iCAP leak out and migrate into uninjected tumors
.

The research team also demonstrated controllable bacterial migration in vivo
.

Next steps

next steps next steps

The group is exploring a range of research areas
.
There are more than 80 different types of CAP present in E.
coli, and even more CAPs are present in other bacterial species that can be engineered using similar methods
.
Furthermore, CAP is not the only molecule on the bacterial surface, other surface molecules can be controlled in a similar way
.
Furthermore, while in this example the iCAP is controlled by an externally provided IPTG, other control systems such as biosensors can be used to autonomously control the surface properties of the therapeutic bacteria
.

There are more than 80 different types of CAP present in E.
coli, and even more CAPs are present in other bacterial species that can be engineered using similar methods
.
Furthermore, CAP is not the only molecule on the bacterial surface, other surface molecules can be controlled in a similar way
.
Furthermore, while in this example the iCAP is controlled by an externally provided IPTG, other control systems such as biosensors can be used to autonomously control the surface properties of the therapeutic bacteria
.

The team, also affiliated with Columbia's Herbert Irving Comprehensive Cancer Center and Data Science Institute, pointed to clinical translation as the next major challenge they hope to address
.
"While there are numerous laboratory studies showing various ways to engineer microbes, applying these powerful therapies to a complex animal or human is extremely difficult," Harimoto said
.
"We have demonstrated proof-of-concept in a mouse model, But given that humans are 250 times more susceptible to bacterial endotoxins than mice, we expect our results may have more impact in human patients than in mice
.
"

But given that humans are 250 times more susceptible to bacterial endotoxins than mice, we expect our results may have more implications for human patients than for mice
.
"

Leong added: "Compared to conventional drug therapies, bacterial cancer therapy possesses unique advantages such as highly efficient tumor tissue targeting and programmable drug release
.
Potential toxicity limits its full potential
.
The 'stealth approach' proposed in this study may address this critical issue
.
"

Bacterial cancer therapy possesses unique advantages such as highly efficient tumor tissue targeting and programmable drug release
.
Potential toxicity limits its full potential
.
The "stealth approach" proposed in this study may address this critical issue
.
"

References:

https://medicalxpress.
com/news/2022-03-invisible-cloak-bacteria-drugs-tumors.
html

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