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Ginger-derived nanoparticles prevent and treat inflammatory bowel disease in mice

By Joseph Bennington-Castro October 3, 2016

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis and Crohn’s disease, are frequently debilitating and difficult to treat. In the last decade, the primary treatment has been systemic anti-inflammatory medications and immunosuppressants that target damaging factors, but these do not provide pro-healing factors to repair the damaged intestine. While these drugs are effective for some people, they sometimes carry harmful side effects, including nausea and pancreatitis. More recently, researchers have investigated drug-carrying synthetic nanoparticles for IBD, but this approach is not without its own issues.

For IBD, scientists in the United States and China have now turned to an age-old natural treatment for gastrointestinal issues: ginger. As described recently in the journal Biomaterials, the international research team fabricated ginger-derived nanoparticles, which not only enhanced the healing of intestinal damage, but also helped prevent acute colitis, chronic colitis, and cancer-associated colitis in mouse models. The ginger-derived nanoparticles (220–290 nm in diameter) represent a novel, natural, nontoxic delivery system, which targets the inflamed intestinal mucosa, blocks damaging factors while promoting pro-healing factors, and could easily be developed for large-scale production aimed at the treatment of IBD, researchers say.

“Ginger is something that exists already in nature and is easy to get and very effective,” says study principle investigator Didier Merlin, a professor at the Institute of Biomedical Sciences at Georgia State University and a research career scientist at the Atlanta Veterans Affairs Medical Center. Because ginger is a natural product, making the nanoparticles requires a less complicated nanotechnology or synthesis process than polymer-based nanoparticles, he says.

Merlin’s research group and others have previously researched the efficacy of synthetic, polymer-based nanoparticles to treat IBD. These nanoparticles, they found, can be used to deliver low doses of drugs to specific cell types and tissues, effectively decreasing systemic side effects from the drugs. But these artificial nanoparticles are difficult to produce on a large scale (important for clinical use) and must be examined for potential in vivo toxicity each time they are chemically modified.

These issues could be overcome by using nanoparticles from certain nontoxic natural sources. Research suggests, for example, that nanoparticles derived from plants, such as grape and grapefruit, are similar to exosomes (cells-derived nano-vesicles) and could be used to deliver drugs to help with gastrointestinal issues and cancers. Merlin and his team wondered if nanoparticles derived from ginger—another natural source, which has the active components 6-gingerol and 6-shogaol that have anti-oxidative, anti-inflammatory, and anti-cancer properties—could be used for IBD. “The traditional approach to bring new therapeutics to the clinic often takes a decade and billions of dollars,” says Jeffrey Karp, a biomedical engineer at Brigham and Women’s Hospital, who was not involved in the research. “The beauty of edible ginger nanoparticles is that it is simple and potentially could reach the clinic faster.”

The team bought fresh ginger roots from three farmers’ markets in Atlanta, Georgia. They thoroughly washed the ginger and then ground it in a blender to produce ginger juice. To remove ginger fibers, they centrifuged the juice at 3000 g for 20 minutes and then at 10,000 g for 40 minutes. Next, they ultracentrifuged (at 150,000 g) the liquid for two hours, and used ultrasonic dispersion to suspend ginger-derived pellets in phosphate-buffered saline. To purify their ginger-derived nanoparticles, they transferred their product into a discontinuous sucrose gradient—a gradient of sucrose concentration—which they ultracentrifuged again, resulting in three layers with three different populations of ginger-derived nanoparticles (GDNP).

Merlin and his team used a number of techniques—including zeta potential analysis, atomic force microscopy, transmission electron microscopy, lipidomic analysis, proteomics, and microRNA sequencing—to fully characterize the biochemistry of their nanoparticles. One population of nanoparticles had zeta potentials close to zero (indicating they are prone to aggregation) and were highly unstable, being unable to survive multiple freeze/thaw cycles—the team excluded this population from further tests. They found that the two other populations, labeled GDNPs 1 and GDNPs 2, had membranes composed mostly of lipids, but with low levels of proteins. “Basically, it’s mostly a bilayer,” Merlin says. Additionally GDNPs 2 had significantly higher levels of 6-gingerol and 6-shogaol than GDNPs 1. Interestingly, tests showed that the nanoparticles retained in the colon of non-starved mice a lot more readily than starved mice. “We don’t really know why that is, but we like it,” Merlin says. “If you want to develop a natural drug, it is more convenient if you don’t have to have the patient starve for 48 hours.”

The researchers tested the medicinal abilities of their nanoparticles, GDNPs 2 in particular, in mouse models of colitis. In one model, they induced acute colon inflammation— a good approximation for ulcerative colitis in people, Merlin says—by giving them the chemical dextran sulfate sodium over 7 days. Mice that were also given GDNPs 2 did not suffer intestinal inflammation (confirmed by histological examinations); tests showed the nanoparticles worked by blocking the production of damaging pro-inflammatory cytokines (a type of immune system signaling protein) and by increasing the production of pro-healing anti-inflammatory cytokines. Furthermore, the nanoparticles promoted intestinal mucosal healing in mice suffering from induced colitis.

In other experiments, the team used “knockout” mice that develop chronic colitis, a model for IBD, 18 weeks after weaning. Mice given GDNPs 2 during development had significantly fewer signs of mucosal inflammation, and the nanoparticles ultimately prevented the progression of the disease. Because colitis-associated cancer is a common complication of ulcerative colitis, Merlin and his colleagues used another model to test the effects of GNDPs 2 on mice with chemically-induced colorectal cancer. The nanoparticles were able to decrease tumor development in the colon by again reducing pro-inflammatory cytokine levels, while also inhibiting the proliferation and apoptosis (cell death) of intestinal epithelial cells.

Huang-Ge Zhang of the University of Louisville, whose research group has recently used ginger nanoparticles to protect mice against alcohol-induced liver damage, believes that the data in the article is solid and convincing. “This finding may lead to clinical application since [an] oral administration approach was taken and edible plant material was used in preclinical models,” he says. However, Karp cautions that while the data is compelling, rigorous human trials are still needed because IBD is a complex disease and animal models do not always predict how treatments will affect people. Laura Ensign-Hodges, a biomedical engineer at Johns Hopkins University, agrees. “There have been numerous examples of the difficulty in extrapolating oral nanoparticle data from mouse to [humans],” she says. “Mice have very different [gastrointestinal] physiology, including higher gastric pH.” But Karp adds: “Hopefully we will soon have an answer.”

Read the abstract in Biomaterials.