It's hard to get meds to the lungs: breathable algae offer a new path

Our lungs are fairly susceptible to diseases. Unlike most other organs, the lungs are in direct contact with the outside world. When we breathe in, our lungs can also take in things besides the oxygen we need, including irritants, pollutants, viruses and bacteria which may cause diseases like pneumonia, bronchitis and cancer.

Fortunately, our respiratory system has special defenses to use against these intruders. Unfortunately, those same defenses can make directly treating the lungs, when they do get sick with those diseases, tricky.

Consider first what a harmful substance, like a bacterium, needs to do before it can even reach our lungs. It must get past the small hairs in our noses that help filter out larger items like dust and pollen. Then it has to escape the mucus in our windpipes that capture particles, which are then swept out by tiny hairs called cilia.

If the bacterium runs the gauntlet and reaches the lungs, then it faces the front line of the immune system: the macrophages. These specialized cells are on the lookout for any unknown substances, which they will engulf and destroy.

So if we want to get something inside the lungs, like medicine to treat a disease like bacterial pneumonia, it has to be small enough to actually reach the lungs and sneaky enough not to be detected and eaten once there. It’s like breaking into a heavily-defensed vault.

That’s why many current lung treatments are actually indirect. Doctors may inject the medicine, like antibiotics to treat pneumonia, into the bloodstream with the hope that some of it will reach the infected lungs. However, because it’s not direct, the patient gets more of the drugs injected than what’s actually needed for the treatment. Those higher doses can have side effects on other parts of the body. For example, taking more antibiotics to treat pneumonia can cause stomach pain and diarrhea.

But recently, UC San Diego chemical and nano engineering researchers have cracked the code to get into the vault directly. They designed tiny drug delivering vehicles that can dodge all the defenses and dive deep inside the lungs.

This sort of breakthrough—which could one day be a game-changing medical treatment—is all thanks to federal funding that allows researchers to push past science fiction and into the vault.

Tiny robots to the rescue

Introducing the microrobot! Microrobots are tiny robots, typically less than 1 millimeter in size and often much smaller. When we think of robots, we might think of some metallic machine in a manufacturing line doing some repetitive tasks that’s too challenging, dangerous or boring for us humans to do. Similarly, microrobots—which in this research are biodegradable and not metallic—are designed to do tasks but in small spaces that humans can’t reach easily or safely.

In this case, researchers—co-led by Joseph Wang, professor in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the UC San Diego Jacobs School of Engineering and world leader in the field of micro- and nanorobotics research—are designing microrobots to travel to the lungs and deliver medicine directly where it’s needed. The first challenge was to figure out what to make the microrobots out of. They needed to be able to move around, and they shouldn’t be made of metal as that’s too much of an irritant for the lungs. So for these reasons, the researchers turned to green algae.

Green algae are plant-like organisms that usually live in water. They are similar to plants because they make their own food through photosynthesis and thus produce oxygen. However, they don’t have the roots or leaves that plants have.

Some types of green algae are microscopic and single-celled, and some of those are able to propel themselves throughout the water. They don’t swim like fish do, but thanks to their whiplike structures called flagella, they have some limited movement. It’s enough movement that they can slip away from being engulfed by the macrophages.

Plus, green algae lack a certain type of structure on their surfaces usually found on bacteria and blue-green algae surfaces. Those structures trigger an immune response, so without them, green algae is safer for biomedical uses.

On these green algae, researchers can load the precise medications needed, like antibiotics to treat bacterial pneumonia. This way, the researchers can use the microrobots to be the deliverers of the specific drugs needed to treat the lung disease. So they speckle each microrobot with dozens of minuscule packets containing the drugs.

Right under the guards' noses

Now that the researchers have figured out that algae would be the microrobotic vehicles to carry their desired lung medications, they faced another challenge: how to get the microrobots into the lungs.

In their latest study, the researchers found that if they picked a small enough algae species, they could put the microrobots into aerosols. The chosen algae are so small that at least 50 of them could line up front to back along the width of a single human hair.

The aerosols, in this study, are small liquid particles that float in the air. When they are made the ideal size, they can easily be taken in by normal breathing through the nose or mouth. At that size, they can evade the defenses of the nose and windpipe and reach the lungs.

Next, the microrobots encounter the invader-detecting macrophages. While the research team picked algae that can be fast enough to “swim” away from the macrophages, they also armed them with a tool to pass under the radar: it basically works like an invisibility cloak.

Remember how the microrobots have tiny packets of drugs on their surface? Those “unknown substances” alone might set off the alarms of the macrophages and thus be destroyed before reaching all parts of the lungs. To avoid that, the researchers gave the packets a coating—the membrane of a cell that’s normally found in the body, like a platelet. It’s a strategy pioneered by Liangfang Zhang, professor in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the UC San Diego Jacobs School of Engineering and co-lead of this research project.

That way, when the macrophages come in contact with the microrobot and its parcels of medicine, they will determine it to be familiar and let it pass. It’s like the microrobot went undercover.

And because they’re not detected and destroyed immediately, the microrobots have the freedom to distribute evenly throughout the lungs, delivering their payloads of drugs. Eventually, with time, the microrobots will be cleared out by the immune system but not before their job is finished. Because they remain active in the lungs on a prolonged schedule, the microrobots give the tiny packets they’re carrying enough time to complete their task: releasing the drugs.

Science fiction no more

So far, these kinds of microrobots to treat lung diseases have only been tried in mice. And the results have been promising; for example, in the latest study on pneumonia in mice, all the mice treated with the microrobots survived, whereas all the mice treated with traditional methods or not at all died within three days.

Colored scanning electron microscope (SEM) image of an algae microrobot (green) carrying drug-loaded nanoparticles (brown). The scale bar is 500 nanometers. Credit: Professor Joseph Wang and Professor Liangfang Zhang Labs

With that kind of success, now human clinical trials using microrobots with an invisibility cloak design similar to this one are foreseeable, and more studies are likely to follow. Just ask the researchers.

“As basic research in microrobotics continues to advance, I expect these technologies will gradually move toward clinical testing for a range of biomedical applications, particularly for the localized and active delivery of medicine,” said Zhang.

While the idea of breathing in tiny robots to treat our lungs may have sounded far-fetched in the past or even straight out of a cartoon, the reality is that years of research are making it possible. Just like in movies where the characters attempt to pull off a large heist from a well-guarded vault, there’s a lot of basic planning and experimenting involved.

But the hard work pays off. In the future, these microrobots may be prescribed to humans. A key advantage is that they could be more effective at treating the disease because they can last a few days inside the lungs and therefore deliver the medicine evenly throughout. Plus, the overall dosage is lower because the medicine goes directly to the lungs rather than through other parts of the body. That reduces side effects from the drugs.

It just goes to show that thanks to research, things that had seemed only science fiction like mobile phones, artificial intelligence and prescription microrobots can become reality.