Technique may improve lung delivery of bacteria-killing phage

July 17, 2018 by John Toon, Georgia Institute of Technology
Image shows a histological section of the mouse lung showing lung cells, with DNA stained blue and microparticles shown in pink. Credit: Rachit Agarwal Garcia Laboratory

A new delivery system for bacteriophages—viruses that selectively attack harmful bacteria—could help give doctors a new way to battle lung infections that threaten older patients and people with cystic fibrosis.

Phage therapy is a promising alternative to antibiotics because it attacks specific pathogens, does not harm the body's normal contingent of bacteria and won't contribute to multi-drug resistance. However, therapeutic bacteriophages can be difficult to purify and challenging to deliver to the site of an infection, especially when that location is the lungs.

A research team headed by the Georgia Institute of Technology has demonstrated a new delivery technique that uses dry, porous microparticles coated with phages. In animal testing, the phage-coated polymer particles successfully treated pneumonia in infected mice and dramatically reduced bacterial levels in an animal model of cystic fibrosis. The technique might one day allow delivery of the dry-powder phage using a device similar to a common inhaler.

Reported July 16 in the journal Nature Biomedical Engineering, the research was supported by the National Institutes of Health and The Children's Healthcare of Atlanta Pediatric Technology Center, a partnership between Georgia Tech and Children's Healthcare of Atlanta.

"Phage delivery is an area where the right type of material could make a difference in therapeutic applications," said Andrés García, the Rae S. and Frank H. Neely Chair and Regents' Professor in Georgia Tech's George W. Woodruff School of Mechanical Engineering. "We set out to engineer a biomaterial carrier that would keep the phage active while delivering them deep into the lungs in a uniform fashion. This is a key step in moving this potential therapy forward."

Phage therapy has generated more interest as concerns about antibiotic use has grown. Specific bacteriophages can target bacteria such as Pseudomonas aeruginosa – which causes some forms of pneumonia and is the major pathogenic bacteria in cystic fibrosis – without affecting other bacteria. Phage activity propagates beyond the coated particles, but is limited by the host population, so once the targeted bacteria are eliminated, the phage disappear.

Researchers have previously used a nebulizer to deliver wet phage mixtures to the lungs, but that approach is inefficient and inconvenient for patients. As an alternative, García and his collaborators developed a microparticle carrier made from the same polymer material used in dissolving sutures. They made the porous particles large enough to avoid rapid clearance by the body, but light enough to be delivered deep into the lungs.

Image shows the effect particles coated with phage (red) have on bacterial colonies (green). The dark green areas around the particles show areas where bacteria are being killed. Credit: Rachit Agarwal, Garcia Laboratory

The phage are incubated on the particles, then dried. When introduced into animal lungs as a puff of dry powder, the phage begin attacking the bacteria. For mice infected with pneumonia, the phage carried on the particles cleared the infection – while untreated mice died. A significant reduction in bacterial populations was observed in transgenic mice whose lungs simulated conditions typical of cystic fibrosis.

"When we immobilized the phage on the particles, we could retain good activity for days – as long as two weeks at room temperature," García said. "We could store these particles, and when we delivered them to mice, get good distribution through the lungs. We believe the particles help stabilize the phage and improve the distribution in the lungs."

Nael McCarty, Marcus Professor of Cystic Fibrosis and director of the Emory+Children's Cystic Fibrosis Center of Excellence at Emory University and Children's Healthcare of Atlanta, and one of the study's co-authors, said the development of the delivery technique potentially advances the use of phage in treatment of cystic fibrosis.

"Cystic fibrosis is a common, life-limiting genetic disorder that affects many organ systems, but the most important impact on human health is chronic infections of the . Bacterial pneumonia that is resistant to multiple drugs is a challenge we must deal with frequently with cystic ," he said. "Treatment with antibiotics often makes space for other opportunistic bacteria to take hold. Phage therapy could complement existing therapies without worsening antibiotic resistance. The technique developed and tested through this important collaboration could address one of the major challenges we have with , which is delivery."

The phage-coated microparticles were more effective at clearing bacteria than dried phage by themselves. The polymer material is biodegradable and was cleared from the animals within a few days. The technique was successful in attacking different strains of bacteria within biofilms, and the researchers did not see evidence that the bacteria were developing resistance.

Though the phage aren't believed to attack mammalian cells, they can create an immune system response, and produce a toxins that can be harmful. They are grown in cultures containing the bacteria they attack, so separating them at the purity levels required is another challenge.

Among the next steps are to test the particle-delivery technique in larger animals and against mixtures of , which often infect humans. The technique must also be tested against chronic infections, which often are seen in persons with .

Explore further: Phage therapy shown to kill drug-resistant superbug

More information: Rachit Agarwal et al. Inhaled bacteriophage-loaded polymeric microparticles ameliorate acute lung infections, Nature Biomedical Engineering (2018). DOI: 10.1038/s41551-018-0263-5

Related Stories

Phage therapy shown to kill drug-resistant superbug

March 13, 2017

Scientists from the University of Liverpool's Institute of Infection and Global Health have shown that phage therapy could offer a safe and effective alternative to antibitotics in the treatment of cystic fibrosis lung infections.

Viruses that infect bacteria abound in bladder

January 29, 2018

Phages—viruses that infect bacteria—are abundant in the bacteria that inhabit the female bladder. This is good news, because phage could be used as alternative treatment when antibiotics become resistant to pathogenic ...

Bacteriophages cure bacterial infections

November 16, 2016

Phage therapy may be a solution to treating infections caused by antibiotic-resistant bacteria. Since 2013, researchers at the University of Helsinki in Finland have collected bacteriophages to combat antibiotic-resistant ...

Recommended for you

The powerful meteor that no one saw (except satellites)

March 19, 2019

At precisely 11:48 am on December 18, 2018, a large space rock heading straight for Earth at a speed of 19 miles per second exploded into a vast ball of fire as it entered the atmosphere, 15.9 miles above the Bering Sea.

Revealing the rules behind virus scaffold construction

March 19, 2019

A team of researchers including Northwestern Engineering faculty has expanded the understanding of how virus shells self-assemble, an important step toward developing techniques that use viruses as vehicles to deliver targeted ...

OSIRIS-REx reveals asteroid Bennu has big surprises

March 19, 2019

A NASA spacecraft that will return a sample of a near-Earth asteroid named Bennu to Earth in 2023 made the first-ever close-up observations of particle plumes erupting from an asteroid's surface. Bennu also revealed itself ...

Nanoscale Lamb wave-driven motors in nonliquid environments

March 19, 2019

Light driven movement is challenging in nonliquid environments as micro-sized objects can experience strong dry adhesion to contact surfaces and resist movement. In a recent study, Jinsheng Lu and co-workers at the College ...

0 comments

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.