Though tiny in stature, a nano-sized particle boasts a large surface area and can be manipulated to deliver drugs to a specific site in the body. The Defense Threat Reduction Agency’s Chemical and Biological Technologies Department (DTRA CB) is supporting researchers at the University of California San Diego (UCSD) in using nanoparticles to deliver an oral vaccine directly to the intestinal walls. Dr. Liangfang Zhang and colleagues at the UCSD have developed this next-generation vaccine-delivery platform that works as intended in mice (a proof of concept). Earlier this year, Zhang and colleagues published an article on this DTRA CB-sponsored research in Nano Letters, a peer-reviewed journal.
Oral vaccines generate a body-wide, longer-lasting immune response, especially when they are absorbed by the mucosal layer, or wall, of the intestine. The absorption stimulates the mucosal cells to produce antibodies called immunoglobulin A (IgA), which induces the desired immunity. However, before oral vaccines can do their work, they must first survive stomach acid. To ensure that a vaccine is directly absorbed by the intestinal wall, researchers are exploring the use of multilayered, self-propelling nanoparticles.
Zhang’s research team built a self-propelling nanoparticle with these ingredients: magnesium nanoparticle, titanium oxide, red blood cells, staphylococcal α-toxin, chitosan, and a stomach-acid repellent.
- The research team started with a nanoparticle of magnesium, a material that creates hydrogen bubbles when exposed to water.
- They coated the magnesium nanoparticle with a titanium oxide layer that includes a small open area to confine the bubbles emitted. The bubbles become propulsive forces, called micromotors, which move nanoparticles deep into the intestine’s mucosal layer.
- The team coated the nanoparticle in Step 2 with a membrane of red blood cells laden with staphylococcal α-toxin. The staphylococcal α-toxin is an antigenic (infection-causing) substance released by the bacterium Staphylococcus aureus. The α-toxin causes pneumonia and other infections in people and other animals. While there is no vaccine against S. aureus, the α-toxin produces short-term immunity in mice from an S. aureus infection. Zhang’s team used the α-toxin as the infection-causing vaccine ingredient, but only to evaluate the micromotor delivery mechanism, not to create a vaccine for S. aureus.
- To ensure that the nanoparticle in Step 3 adheres to the intestinal walls, the team added a layer of chitosan (sugar that comes from fish).
- The team coated the nanoparticle in Step 4 with a substance to protect the nanoparticle from the stomach’s acidic environment. The resulting product is a multilayered nanotoxoid.
Once administered, the nanotoxoid travels from the mouth to the intestine. Along the way, it sheds each of its layers until the membrane of red blood cells and α-toxin attaches to the intestinal wall.
Zhang’s research team tested the nanotoxoid for two outcomes. The first outcome was to ensure that the multilayered micromotor nanotoxoids attached to a mouse’s intestinal wall. The team fed the nanotoxoids to mice and performed an imaging analysis of the rodents’ gastrointestinal tracts by using a dye to track the nanotoxoids. Nanotoxoids safely passed through the stomach, and the mice retained a significant amount of nanotoxoids in their intestinal walls.
The team then focused on the second outcome of interest: whether the nanotoxoids stimulated an immune response in the intestinal wall to produce IgA antibodies. A healthy mouse has a low number of IgA antibodies, but this number increases when the mouse is fighting an infection. If the α-toxin-bearing nanotoxoids adhere to the intestinal walls as intended, then they would activate the mucosal immunity in mice, and the number of IgA antibodies would be higher than normal. To test this assertion, Zhang’s team conducted a case-control study with another group of mice. Case mice were fed the micromotor nanotoxoids, and the control mice were fed static nanotoxoids. Similar to a pill-based oral vaccine, the static nanotoxoids included the infection-causing α-toxin as the vaccine but not the magnesium that produces self-propulsion. After one week, the research team analyzed the mice’s feces for the number of IgA antibodies. IgA antibodies were 10 times higher among mice in the case group than among mice in the control group. The micromotor nanotoxoids delivered the α-toxin to the intestinal walls better than the static nanotoxoids did.
The work of Zhang and colleagues, supported by DTRA CB, has resulted in a new platform for delivering oral vaccines. This new platform has the potential to encourage improvements in the delivery of oral vaccines currently on the market and to serve as an impetus for formulating new vaccines. Both accomplishments would ensure that warfighters are less vulnerable to disease on the battlefield.
|Date Posted:||12.13.2019 11:29|
|Location:||FORT BELVOIR, VA, US|
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