February 26, 2024

An antibiotic that you inhale can deliver medicine deep into the lungs

Since Covid-19, we have all become more aware of lung health.

However, for people with asthma and chronic obstructive pulmonary disease (COPD), dealing with lung problems is a lifelong struggle. Those with COPD suffer from highly inflamed lung tissue that swells and blocks the airways, making it difficult to breathe. The disease is common, with more than three million cases reported annually in the US alone.

Although manageable, there is no cure. One problem is that with COPD, the lungs pump out tons of viscous mucus, which creates a barrier that prevents treatments from reaching the lung cells. The slimy substance, if not coughed out, also attracts bacteria, further aggravating the condition.

A new study in Scientific progress describes a possible solution. Scientists have developed a nanocarrier to transport antibiotics to the lungs. Like a biological spaceship, the wearer has ‘doors’ that open and release antibiotics into the mucus layer to fight infections.

The ‘doors’ themselves are also deadly. Made of a small protein, they tear apart bacterial membranes and clear their DNA to rid lung cells of chronic infections.

The team developed an inhalable version of an antibiotic using the nanocarrier. In a mouse model of COPD, the treatment revived their lung cells in just three days. The oxygen levels in their blood returned to normal and previous signs of lung damage slowly healed.

“This immunoantibacterial strategy may change the current paradigm of COPD management,” the team wrote in the article.

Breathe for me

Lungs are extremely vulnerable. Imagine thin but flexible layers of cells, separated into lobes, to help coordinate the flow of oxygen to the body. Once air passes through the trachea, it quickly spreads through a complex network of branches, filling thousands of air sacs that supply the body with oxygen while removing carbon dioxide.

These structures are easily damaged and smoking is a common trigger. Cigarette smoke causes surrounding cells to pump out a slimy substance that blocks the airways and covers the air sacs, making it difficult for them to function normally.

Over time, the mucus builds up a kind of ‘glue’ that attracts bacteria and condenses into a biofilm. The barrier further blocks oxygen exchange and changes the environment of the lungs into one favorable to bacterial growth.

One way to stop the downward spiral is to eradicate the bacteria. Broad-spectrum antibiotics are the most commonly used treatment. But because of the slimy protective layer, they cannot easily reach bacteria deep in the lung tissue. Worse, long-term treatment increases the risk of antibiotic resistance, making it even more difficult to eradicate stubborn bacteria.

But the protective layer has a weakness: it’s just a bit too acidic. Literal.

Open door policy

Like a lemon, the mucus layer is slightly more acidic compared to healthy lung tissue. This quirk gave the team an idea for an ideal antibiotic carrier that would release its payload only in an acidic environment.

The team made hollow nanoparticles from silica – a flexible biomaterial – filled them with a common antibiotic and added ‘doors’ to release the drugs.

These openings are controlled by additional short protein sequences that act as ‘locks’. In normal airway and lung environments, they fold at the door, effectively trapping the antibiotics in the bubble.

The local acidity released in the lungs in COPD changes the structure of the lock protein so that the doors open and antibiotics are released directly into the mucus and biofilm – essentially breaking through bacterial defenses and targeting them on their home turf.

One test of the concoction penetrated a lab-grown biofilm in a petri dish. It was much more effective compared to an earlier type of nanoparticle, largely because the carrier doors opened once inside the biofilm – other nanoparticles trapped the antibiotics.

The carriers could also dig deeper into infected areas. Cells have electrical charges. The carrier and the slime both have negative charges, which – like the similarly charged ends of two magnets – push the carriers deeper into and through the slime and biofilm layers.

Along the way, the acidity of the mucus slowly changes the carrier’s charge to positive, so that once it gets past the biofilm, the “lock” mechanism opens and medication is released.

The team also tested the nanoparticle’s ability to eradicate bacteria. In one dish, they destroyed several common types of infectious bacteria and destroyed their biofilms. The treatment seemed relatively safe. Tests using human fetal lung cells in a dish found minimal signs of toxicity.

Surprisingly, the wearer itself could also destroy bacteria. In an acidic environment, the positive charge broke down bacterial membranes. Like exploded balloons, the insects released genetic material into their environment, which the carrier swept up.

Dampen the fire

Bacterial infections in the lungs attract overactive immune cells, leading to swelling. Blood vessels around the air sacs also become permeable, making it easier for dangerous molecules to pass through. These changes cause inflammation, making it difficult to breathe.

In a mouse model of COPD, treatment with inhalable nanoparticles calmed the overactive immune system. Multiple types of immune cells returned to healthy activation levels, allowing the mice to switch from a highly inflammatory profile to one that fights infection and inflammation.

Mice treated with the inhalable nanoparticle had about 98 percent fewer bacteria in their lungs, compared to mice given the same antibiotic without the vehicle.

Eradicating bacteria gave the mice a sigh of relief. They breathed easier. Their blood oxygen levels rose and blood acidity – a sign of dangerously low oxygen levels – returned to normal.

Under the microscope, the treated lungs recovered normal structures, with firmer air sacs slowly recovering from COPD damage. The treated mice also had less swelling in their lungs due to fluid buildup, which is common with lung injuries.

Although the results are promising, they only apply to a smoking-related COPD model in mice. There is still a lot we don’t know about the long-term effects of treatment.

Although there were no signs of side effects so far, it is possible that the nanoparticles could build up in the lungs over time and eventually cause damage. And although the carrier itself damages bacterial membranes, the therapy is largely dependent on the encapsulated antibiotic. As resistance to antibiotics increases, some medications are already losing their effect in COPD.

Then there is a chance of mechanical damage over time. Repeatedly inhaling silicon-based nanoparticles can cause long-term lung scarring. So while nanoparticles could change COPD management strategies, it’s clear we need follow-up studies, the team wrote.

Image credits: crystallight / Shutterstock.com

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