Nanoengineers at the University of California, San Diego have demonstrated for the first time the use of micromotors to treat a bacterial infection in the stomach. These tiny vehicles, each about half the width of a human hair, swim rapidly throughout the stomach while neutralizing gastric acid and then release their cargo of antibiotics at the desired pH. [Laboratory for Nanobioelectronics/UCSD]

Scientists have for the first time used tiny self-propelling, drug-loaded micromotors to treat a bacterial gastric infection in experimental mice, without the use of acid-blocking proton pump inhibitors (PPIs). Developed by researchers at the University of California, San Diego (UCSD), the biodegradeable micromotors are less than half the width of a human hair in size and constructed around a magnesium (Mg) core that reacts with protons in stomach acid to propel the vehicles to the stomach wall, where they attach and release their antibiotic cargo. And because the micromotors use protons as fuel, they have the added benefit of neutralizing gastric acid, which helps to increase antibiotic effectiveness by preventing drug degradation.

In a paper in Nature Communications, a team led by Joseph Wang, D.Sc., and Liangfang Zhang, Ph.D., at the UCSD Jacobs School of Engineering, describe the use of clarithromycin (CLR)-loaded micromotors to treat a mouse model of Helicobacter pylori infection. Their paper is entitled, “Micromotor-Enabled Active Drug Delivery for In Vivo Treatment of Stomach Infection.”

About 50% of the world's population will harbor an H. pylori infection, which can cause a range of gastric and extragastric diseases, the authors explain. Treatment usually involves a course of antibiotics in combination with a PPI to reduce gastric acid production, which otherwise reduces antibiotic effectiveness. Unfortunately, long-term use of PPIs can lead to side effects ranging form headache and diarrhea to anxiety and depression, so approaches to antibiotic therapy that don’t require PPIs are needed.

The USCD team had previously developed zinc-based and Mg-based micromotors that can self-propel in the stomach and intestinal fluids. For their in vivo therapeutic studies, they developed biodegradable micromotors comprising a 20-μm-diameter magnesium core, wrapped in a protective titanium dioxide coating, which is then overlaid with a CLR-loaded poly(lactic-co-glycolic acid) (PLGA) film and a chitosan polymer layer. The positively charged chitosan outer coating helps the motors to stick to the stomach wall, where the antibiotic is released from the PLGA polymer coating.

The micromotors use up protons from gastric fluid as they propel themselves through the stomach, and this raises the local gastric pH to neutral within about 20 minutes. Acid neutralization helps to prevent antibiotic degradation and ensure that the delivered drug is as effective as possible, without the use of PPIs. The Mg core also dissolves gradually as the micromotors are propelled along, so the active drug carriers have a self-limiting lifespan of about 6 minutes and effectively self-destruct without leaving any harmful residues. Normal stomach pH is restored within about 24 hours.

The team first carried out a number of in vitro studies to confirm that the Mg-based micromotors could propel themselves through gastric acid, and also to optimize drug loading and to test the bactericidal activity of antibiotic-carrying micromotors. They were able to visualize how the hydrogen bubbles generated by the Mg-acid reaction propelled the micromotors along with an average speed of about 120 μms–1

Initial in vivo studies then confirmed that dye-loaded micromotors distributed evenly throughout the stomach and attached to the stomach wall, including the antrum, which is where H. pylori bacteria reside. “The powerful propulsion leads to tissue penetration and binding, so that the drug-loaded motor could reach the whole stomach wall for enhanced retention,” the authors write in their published paper.

The UCSD team moved on to test their antibiotic-loaded micromotors in a mouse model of H. pylori infection. Their results demonstrated that the CLR-loaded microvehicles were at least as effective at reducing bacterial burden as treatment using orally administered CLR plus PPI therapy. “Although the difference between CLR-loaded Mg-based micromotors and the free CLR+PPI groups was not statistically significant, the CLR-loaded micromotors reduced the H. pylori burden in mice compared with in the negative controls by ~1.8 orders of magnitude, whereas the free CLR+PPI group reduced it only by ~0.8 orders of magnitude,” the authors stress.

The team projects that drug-loaded micromotors could be developed as safe treatments for other stomach diseases, in addition to H. pylori infections. “As our early studies have shown that the Mg-based micromotors can propel efficiently and position precisely in the gastrointestinal (GI) tract, we believe the presented motor-enabled delivery approach is promising to treat diverse GI tract diseases,” they write.

The researchers also envisage that the micromotor concept could be adapted to enable active delivery of drugs to other tissues and to eliminate hard-to-treat bacterial biofilms. “Extending the propulsion methods with new alternative biocompatible fuels or fuel-free actuation might be able to expand the active-delivery concept to different parts of the body.”

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