One of the most engaging areas of research these days is improving drug delivery. Here at Medgadget, we often share news about technological advances in nanomedicine that promise improved delivery to tumor sites, or newly designed gadgets that increase drug delivering efficacy. Rarely do we hear about attempts to improve drug delivery in the lungs. Recent reports suggest that almost 7% of all US deaths are due to chronic respiratory diseases, making them the fifth leading cause of death. Thankfully, a team of researchers from Carnegie Mellon has recently taken on the challenging task of improving drug delivery in the complex lung environment. Medgadget had a chance to chat with Dr. Diane Nelson, one of the lead researchers working on the novel technology.
Mohammad Saleh, Medgadget: Tell us about the problem that your research is trying to solve.
Diane Nelson, Carnegie Mellon: There are many lung diseases that cause the lungs to be filled with either some type of fluid or mucus that makes breathing really difficult. For example, one of these is cystic fibrosis. Patients create a lot of really thick mucus in their lungs, which builds up, constricts airways, and makes it difficult to breathe. Furthermore, this thickened mucus effectively traps bacteria and other pathogens, making these patients prone to chronic lung infections. Another condition is acute lung injury, which is a severe inflammatory response to a lung injury and then the lungs are flooded with inflammatory fluid. This affects the lungs because this fluid then blocks oxygen flow from the air in the lungs to your blood vessels. Drugs like growth factors and anti-inflammatories are needed to rapidly heal the injury and return the lung to normal function.
Medgadget: How are COPD/cystic fibrosis drugs currently delivered/administered? Problems with this delivery method?
Nelson: In many of these cases, the standard method of treatment right now is inhaled drug delivery. The patients would inhale drugs or antibiotics, and it would be deposited throughout the lung. The problem is the delivery method. These patients can’t breathe, but the medicine can only be delivered well if they’re inhaling deeply. If you can’t inhale deeply how would you get around that? You can’t go in there and scoop out any of the fluid that’s in there blocking their airways. You’d have to wait for it to resolve on its own – which may take too long and is counterproductive. The only other alternative is to then deliver the drugs into the bloodstream, but this has major setbacks: (1) you have to deliver more drug because it becomes diluted in all the blood and (2) this higher dose of drug considerably increases the risk of toxicity, especially in the case of antibiotics.
Medgadget: Tell us about your proposed new drug delivery technique that you’ve designed. Why do you think it’s superior to the current standard of care?
Nelson: The method that we’re proposing is to deliver these drugs by filling the lungs with another liquid. It’s a two-fold approach – the main function of this is to perform a lung lavage so we’re actually washing out that mucus or fluid that’s causing this initial decrease in gas exchange. The second step would be to then deliver whatever drugs the patient needs. Whenever people hear that we’re putting fluid in the lungs, they think that’s a bad thing because it would decrease your ability to get oxygen, like drowning. But, the fluid that we’re using is called perfluorocarbon (PFC), and it’s really unique because it can dissolve a lot of oxygen and carbon dioxide.
You can saturate it with oxygen first and then put it into the patient’s lungs. The body uses that oxygen the same way it would if it was sitting in your lungs as air. PFC also has a really high density, which allows it to actually wash out the other fluids in the lung. Anything that’s similar to the consistency of water will float to the top to be suctioned out and the PFC will go to the bottom to deliver oxygen and drugs.
Medgadget: Do you then dissolve the drugs in this PFC solution?
Nelson: That’s where the real research is. The problem is that PFC is not soluble with most drugs, with water, nor with oil. You can’t just create a mixture of drugs and put them into the PFC and deliver it uniformly. We have to use what’s called a surfactant (a surface-active agent) that sits at the interface between the two liquids.
We dissolve the drug in water or oil or whatever it’s normally delivered in. Then we emulsify (or carefully suspend) the drug-carrying solution into the PFC liquid, and we do that using surfactants. The surfactant molecules are two-sided with one water-loving side and one PFC-loving, and that’s how it stabilizes at the interface. We get some relatively stable droplets that are uniformly mixed into the PFC liquid and then could be delivered to the patient.
However, you must optimize the surfactant: too much stability and the droplet will never break open and release the drug, too little stability and the drug solution will quickly separate and float to the top with the other mucus and be suctioned out. The research focused on finding this optimal concentration that you can use to get pseudo-stable droplets. They’re initially a uniform distribution, but as they hit into the wall lining, they start to break open a lot faster.
Medgadget: How are PFCs evacuated from the lung?
Nelson: We would suction the majority of it out after treatment. At least two-thirds of the PFC can be removed from the lung. But another property of PFC is that it evaporates at or below body temperature. Anything that’s left over after suctioning is simply exhaled. In our studies, we’ve seen rats that were able to breathe on their own after two hours.
Medgadget: Wouldn’t you lose the native surfactant that’s crucial for the function of the lung?
Nelson: There have been several studies looking to see whether or not this delivery method washes out the native surfactant lining of a healthy lung. But it doesn’t – it just slides right across it!
Medgadget: What are PFCs currently used for in clinical settings?
Nelson: There isn’t an FDA approved use for PFCs in the clinic. There’s a lot of research that’s being done with it. One of the main ones it’s being used for is for premature infants – they don’t have fully developed lungs and thus lack the native surfactant. This method of filling your lungs with this liquid is a gentler way to help ventilate their lungs. That has been used in several cases as a last resource and has led to survival of the babies.
There are other uses for PFCs as well. They’ve been looked into for blood substitutions, in which the bulk liquid would be an aqueous solution and then the droplets would be PFCs. In this case they can act like red blood cells to carry oxygen and help oxygenate ischemic tissues or help with wound repair.
Medgadget: Walk us through some of the tests/experiments you’ve carried out to validate this work.
Nelson: To begin with, we’ve taken antibiotics, emulsified them into PFC liquids and delivered them to bacteria to see how well they’re killing. We’ve also used this to optimize our emulsion formulation – so basically how much drug do we need, how much water, and how long do we need to leave it on.
Given that this was successful, we moved to animal trials where we would infect rats and rabbits, instead of a petri dish. Initially, we used a lot of surfactant to test really stable emulsions – but we weren’t able to kill any of the bacteria infecting the lungs because the antibiotic wasn’t being released. We adapted the system and were able to successfully decrease the number of bacteria in a rat’s lung and it performed just as well as the standard-of-care treatment, which is inhaled antibiotics.
The final piece to try to expand our project was to start delivering growth factors to see how our PFC emulsions affected cells. To heal an acute lung injury, you need to activate some wound healing and cell migration pathways. In order to do that, you need lots of growth factors and anti-inflammatory molecules. The chemistry and size of these drugs affect the efficacy of the emulsions. Some growth factors are highly time- and concentration-dependent. For the last bit of this research, we created these emulsions with one growth factor, lysophosphatidic acid, or LPA, which is capable of enhancing cell migration, proliferation, and barrier function. We found that LPA-loaded particles work really great in a petri dish, particularly for improving cell migration. However, more tailoring needs to be done for it to get the type of response that we’d want, but we can successfully deliver a growth factor.
Medgadget: What do you think needs to happen for this technique to become the gold standard for drug delivery to the lungs?
Nelson: A lot. The mechanism needs to be understood in a lot more detail. What happens with the fluorosurfactant? We know that the PFC is going to be exhaled, but the fluorosurfactant is not. How is the body affected by that?
Emulsifying drugs doesn’t seem to be a problem – people have emulsified insulin, a pretty large protein, and even stem cells.
This emulsification system is currently being looked at for high throughput screening of drug products. You can emulsify the target cells along with the drug and characterize the responses in a high throughput manner.
Another difficulty is the way that this treatment would be performed in the clinic. Filling the patient’s lungs with liquid, would be really uncomfortable – even though they’re getting the oxygen they need. Patients would generally need to be sedated, so this would not be a first approach to treating a given lung disease because it requires so much more work. You have to be watching the patient constantly, and it’s a very invasive procedure – it’s more applicable for severe end-stage cases.
Luckily, there’s also the possibility of aerosolizing these PFC emulsions carrying a drug, which actually works a little bit better than just inhaling the drug because the PFC emulsions are more stable. In this case, any patient capable of breathing on their own could participate. You don’t have to completely fill the lung for patients to benefit from PFCs in their lungs. However, we wouldn’t be able to wash anything out of their lungs since they are only inhaling a small volume.
