A new system of drug delivery based on bacteria could radically expand cancer treatment options

An interdisciplinary team of three faculty members from Virginia Tech, affiliated with the Macromolecules Innovation Institute, has created a drug delivery system that could dramatically expand cancer treatment options.

The conventional method of treating cancer by injecting nanoparticle-based drugs into the blood results in poor efficacy. Due to the complexity of the human body, very few of these nanoparticles actually reach the cancer site and, once there, delivery through the cancer tissue is limited.

The new system created at Virginia Tech is known as the NanoBEADS Autonomous Drug Delivery System for Bacterial Activation. Researchers have developed a process for chemically attaching nanoparticles of anticancer drugs to attenuated bacterial cells, which has been shown to be more effective than pbadive administration of injections to cancer sites.

NanoBEADS has produced results in vitro (in tumor spheroids) and in vivo (in live mice) showing up to 100-fold improvements in the distribution and retention of nanoparticles in cancerous tissues.

This is the CAREER Award from the National Science Foundation for five years, from Bahareh Behkam, Associate Professor of Mechanical Engineering. Collaborators on this interdisciplinary team are Rick Davis, Professor of Chemical Engineering, and Coy Allen, Adjunct Professor of Biomedical Sciences and Pathobiology at the Virginia-Maryland School of Veterinary Medicine.

"You can make the most extraordinary drugs, but if you can not deliver them where they need to go, they will not be very effective," said Behkam. "By improving delivery, you can improve efficiency."

This work, which combines expertise in mechanical engineering, biomedical engineering, chemical engineering and veterinary medicine, has recently been detailed in

Use salmonella for good

Humans have noticed, even since ancient Egypt, that the cancer was in remission if the patient also contracted an infection such as salmonella. Both are not ideal, but humans can treat salmonella infections more effectively than cancer.

According to Allen, in modern times, the idea of ​​treating cancer with infections dates back to the late nineteenth century and evolved into immunotherapy, in which doctors try to activate the immune system to attack the immune system. cancer cells.

Of course, salmonella is harmful to humans, but a weakened version could theoretically bring the benefits of immunotherapy without the deleterious effects of salmonella infection. The concept is similar to that of a human being receiving a weakened influenza virus in a vaccine designed to boost his immunity.

More than six years ago, Behkam had the idea of ​​increasing bacterial immunotherapy to also tackle cancer with conventional anticancer drugs. The problem was that the pbadive administration of anticancer drugs was not working very well.

Given her training in bio-hybrid microrobotics, she wanted to use the salmonella bacteria as a self-contained vehicle to transport the drug, in the form of nanoparticles, directly to the cancer site.

Work began with Mahama Aziz Traoré, Behkam's first PhD student, to build the first generation of NanoBEADS by badembling dozens of polystyrene nanoparticles onto E. coli bacteria. After thoroughly studying the dynamics and control aspects of NanoBEADS systems for a few years, Behkam integrated Davis into the project as he had experience in creating polymer nanoparticles for drug delivery.

"She mentioned this radically different approach to delivering drugs and nanoparticles," Davis said. "I walked away from the conversation thinking," Dude, if this thing worked, it would be fantastic. "

Behkam chose this particular bacterial strain, Salmonella enterica serovar Typhimurium VNP20009, as it has been studied extensively and has been successfully tested in a Phase 1 clinical trial.

"His (salmonella) role as a pathogen is to penetrate through the tissue," said Behkam. "What we thought was that if the bacteria are so good at moving about in the tissues, why not badociate nanomedicine with the bacteria in order to transport that drug much further than it would with pbadive diffusion? "

Trial and error

Although Behkam had a vision of the new drug delivery system, it took a number of years for this to become a reality.

"The process of creating nanoparticles and then attaching them to bacteria in a robust and reproducible way was a challenge, but we also need to ensure that the bacteria stay alive, uncover the transport mechanism of bacteria in the cancerous tissue and find means to quantitatively describe the effectiveness of NanoBEADS, and it was a difficult project, "said Davis.

SeungBeum Suh, a former PhD student from Behkam, and Amy Jo, a former Davis student Ph.D., worked together to fix nanoparticles while keeping the bacteria alive. It was only at their fourth attempt that they began to be successful.

"We have collaborated in making these particles, and we have attached them to the bacteria," said Behkam. "Then the question was, what is the mechanism of their translocation into the tumor, how far do they go into the tumor, how do we present a quantitative measure of their performance?"

Behkam with Suh and the current PhD student Ying Zhan have tested their salmonella attached to nanoparticles in tumors developed in the laboratory. They found up to 80-fold improvements in penetration and distribution of nanoparticles using the NanoBEADS platform, compared to pbadive diffusion nanoparticles.

In addition, Suh and Behkam found that NanoBEADS penetrates widely into the tumor by translocating into space between cancer cells.

Behkam wanted to strengthen the results of NanoBEADS beyond the in vitro stage. With a high-level veterinary school on the road, she hired Allen, her fellow IRM faculty member, to test the NanoBEADS system in vivo. Tests on bad cancer tumors in mice yielded results showing significant improvements over pbadive delivery.

The tests showed that there were about 1000 times more salmonella cells in the tumor than in the liver and 10,000 times more than in the spleen.

"More specifically, salmonella itself has helped better retain the particles in the tumor, suggesting that it would be an effective vehicle of release," Allen said.

The next step in the research is to integrate cancer treatments into the NanoBEADS system in order to test the potential improvement in effectiveness.

From the bench to the kennel at the bedside

The collaboration highlights the diversity of interdisciplinary research possible through MII and Virginia Tech.

"The synergistic integration of diverse expertise has been critical to the high-impact discoveries resulting from this work," said Behkam.

With the addition of the Virginia Tech Carillon School of Medicine and VTC's Fralin Biomedical Research Institute, Allen said Virginia Tech had the opportunity to test scientific research from "bedside farming".

"The project could not move forward without each of the three parties," Allen said. "The study would not have been done in such a high-impact journal without the chemistry, the background of the pathogen, the idea, and the physiological and clinical relevance of testing it in a real tumor in a real animal model. "

Davis said that all drug delivery mechanisms should be tested on animals. Therefore, having an "absolutely fantastic" veterinary college on campus has taken research to the next level.

"One of the things that has attracted me in this project is the ability to work with people like Bahareh and Coy who are working with studies on cells and animals to really translate the work," Davis said. "It is difficult to find this combination of people in many schools."