Nanoparticle-coated bacteria can deliver cancer vaccine

April 16, 2015 by Lisa Zyga, Medical Xpress feature
Nanoparticle-coated bacteria can act as a vaccine vector, delivering vaccines that evoke an antitumor immune response. As shown here, the nanoparticles are made from cationic polymers and the bacteria’s plasmid DNA. The positively charged nanoparticles self-assemble onto the negatively charged bacterial cell walls. Credit: Hu, et al. ©2015 American Chemical Society

Marking an important step in the development of immunotherapy cancer treatment, scientists have demonstrated that nanoparticle-coated bacteria can effectively deliver an oral DNA vaccine that stimulates the body's own immune system to destroy its cancer cells. This is the first time that a nanoparticle coating has been used for bacterial delivery of oral DNA vaccination in vivo. Compared with uncoated bacteria, coated bacteria can bypass many of the roadblocks that have so far limited the immune response and that currently pose the biggest challenge to DNA vaccinations against cancer.

The researchers, led by Yuan Ping at Nanyang Technological University in Singapore and Guping Tang at Zhejiang University in Hangzhou, China, have published their study on using the nanoparticle-coated bacteria for oral DNA vaccines in a recent issue of Nano Letters.

"The most significant aspect of our work is to provide an important delivery solution to effectively improve the oral bioavailability of cancer vaccines," Ping told "Although some delivery materials that are able to protect antigen in transit through the stomach and gut for oral vaccination have long been investigated, only a few could successfully surmount substantial hurdles to oral vaccine development. Our engineered 'living materials' that combine the advantages of live cells with non-living nanomaterials successfully break the bottlenecks of oral DNA vaccines delivery, and have produced a new method of treating cancer that effectively increases the strength of immune responses against tumors by stimulating the activities of specific components of the immune system."

Helpful bacterial infections

In general, immunotherapy is considered to be a promising alternative to current forms of cancer treatment such as chemotherapy and radiation, which directly attack and destroy cancer cells but often damage healthy cells in the process. Because immunotherapy stimulates the body's own immune system to target and destroy cancer cells, it has the potential to be much safer and cause fewer side effects than other treatments.

One oral DNA vaccine that researchers have been working on is called NP/SAL, which suppresses tumor angiogenesis (). Many tumors secrete angiogenic factors such as vascular endothelial growth factor (VEGF) to promote blood vessel formation, which can eventually lead to tumor metastasis. The NP/SAL vaccine stimulates the immune system to produce T cells () and cytokines (chemical messengers), which in turn interfere with the VEGF pathway, reducing blood vessel formation and ultimately inhibiting tumor growth.

Although this strategy is effective if it can evoke a sufficiently strong immune response, the challenge lies in getting the vaccine to the right place, which is the lower gut, from where it is disseminated into the blood. One way to do this is by inserting the vaccine into the DNA of live bacteria such as Salmonellae that have been attenuated, i.e., their toxicity has been reduced to safe levels. When the vaccine (carried by the bacteria) is administered to a patient, the bacteria invade the body as in a typical bacterial infection, colonizing, reproducing, and spreading their DNA and the vaccine with it.

Before the vaccine can evoke the desired immune response, however, it must overcome two major hurdles. First, the bacteria encounter a common immune response in which white blood cells called macrophages engulf the foreign invaders and trap them inside vesicles called phagosomes. Few bacteria can escape the phagosomes, and those that do must encounter the highly acidic environment of the stomach and intestines. Only a small percentage of the original bacteria make it past these two hurdles, which are the key reasons for the failure of the vaccine to date.

Illustration of the process by which nanoparticle-coated Salmonellae deliver an oral DNA vaccine, NP/SAL, to activate an antitumor immune response. Credit: Hu, et al. ©2015 American Chemical Society

Nanoparticle coating

In the new paper, the researchers show for the first time that nanoparticle-coated bacteria have a much better chance than uncoated bacteria of overcoming these two hurdles and evoking a significantly stronger . The nanoparticles contain positively charged polymers, which self-assemble onto the negatively charged cell walls of the Salmonellae due to electrostatic interactions. The coated bacteria can better tolerate the acidic stomach and intestines, partly because the coating acts as a buffer, resisting changes in pH, and partly due to the physical protection it offers. The coating also helps the bacteria escape the phagosomes because the cationic polymers initiate a "proton sponge effect," soaking up protons and causing the phagosomes to swell and rupture due to osmosis.

Due to these advantages, the nanoparticle-coated bacteria are more likely to reach the lower gut to initiate the desired infection. The researchers found that 60% of mice vaccinated with NP/SAL carried by nanoparticle-coated bacteria survived the full 35-day study duration without tumor growth. The mice also lost almost no body weight, reflecting the low toxicity of the vaccine.

The researchers expect that this strategy of using nanoparticle-coated bacteria as DNA vaccine vectors can be applied to a wide variety of vaccines, and potentially used to treat a wide spectrum of cancers. As Ping explained, these opportunities would not have been possible without recent research on understanding the immune system.

"Immunotherapeutic agents have provided limited evidence of clinical success until recent advances in understanding how escape recognition and attack by the ," Ping said. "This offers many opportunities for scientists to rationally design vaccines which can accomplish cancer immunotherapy. Because bacterial coatings can be simply achieved by the self-assembly between bacteria and nanoparticles, we expect that this type of vaccine can be used as traditional 'drug in the vial' type formulations for patients in clinical settings in the next 3-5 years."

In the future, the researchers plan to experiment with different combinations of bacteria and vaccines to target specific applications.

"Our future research aims to engineer different nanoparticle-coated bacteria, which are expected to cover other types of cancer and immunodeficiency disorders," Ping said. "Because there are quite a few choices besides Salmonella, and also a large number of functional nanoparticles available, we expect to engineer different types of vaccines that are precisely tailored for more specific applications. The adaptable and versatile properties of this vaccine design strategy opens up new possibilities for treating a wide spectrum of immunological diseases in the dawning era of personalized nanomedicine."

Explore further: Clinical trials of VPM1002 as a tuberculosis vaccine in newborns

More information: Qinglian Hu, et al. "Engineering Nanoparticle-Coated Bacteria as Oral DNA Vaccines for Cancer Immunotherapy." Nano Letters. DOI: 10.1021/acs.nanolett.5b00570

Related Stories

Clinical trials of VPM1002 as a tuberculosis vaccine in newborns

March 24, 2015
The only tuberculosis vaccine currently approved, the Bacillus Calmette-Guérin (BCG) vaccine, protects children from the most severe forms of the disease in most cases but does not provide protection against the most common ...

Bacteria protect intestinal tumor model from being killed by immune cells

February 11, 2015
Bacteria that are commonly found in the mouth are often abundant in patients with colon cancer, but the potential role these microbes play in tumor development has not been clear. A study published by Cell Press February ...

Protein serves as a natural boost for immune system fight against tumors

January 30, 2014
Substances called adjuvants that enhance the body's immune response are critical to getting the most out of vaccines. These boosters stimulate the regular production of antibodies—caused by foreign substances in the body—toxins, ...

Researchers reprogram tumor's cells to attack itself

February 4, 2015
Inserting a specific strain of bacteria into the microenvironment of aggressive ovarian cancer transforms the behavior of tumor cells from suppression to immunostimulation, researchers at Norris Cotton Cancer Center and the ...

Vaccines may make war on cancer personal

November 26, 2014
In the near future, physicians may treat some cancer patients with personalized vaccines that spur their immune systems to attack malignant tumors. New research led by scientists at Washington University School of Medicine ...

Can cancer vaccines prolong survival?

April 6, 2015
Therapeutic anti-cancer vaccines developed to treat metastatic disease such as advanced prostate cancer or melanoma rarely have a noticeable effect on the tumor but have been associated with a statistically significant increase ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.