Scientists have tracked the flow of nanoparticles from the lungs to the bloodstream for the first time. The work could lead to the development of new drugs and help researchers understand how pollution can cause respiratory problems.
Researchers from Beth Israel Deaconess Medical Center and the Harvard School of Public Health injected fluorescent nanoparticles into rats’ lungs and used near-infrared imaging to watch as the particles moved through their bodies. The researchers tracked how far—and how quickly—nanoparticles of different size, shape, and surface charge were able to travel after being injected. They found that nanoparticles between six and 34 nanometers in diameter were able to get past the lung’s defenses to reach the lymph nodes and the bloodstream. This finding may provide valuable guidelines for designing nanoparticle-based drugs.
The minuscule size of nanoparticles makes them potentially useful for delivering drugs. A drug needs to get through tissue barriers and fight off the body’s attacking immune cells to deliver its therapeutic payload before exiting the body to prevent a toxic reaction. Scientists are manipulating the size, shape, and other characteristics of nanoparticles to find the right combination that will carry them effectively through the body.
“There’s a learning curve that all of us are going through,” says Steven Brody, associate professor of medicine at Washington University School of Medicine. “When we start designing nanoparticles as drug-delivery vehicles, we need to start understanding what the rules are. This starts to give us some rules.”
Akira Tsuda, principal research scientist at the Harvard School of Public Health, says the lungs can be a good entry point for drugs: they have a large, thin surface area through which drugs can cross into the rest of the body. But the lungs also have powerful defensive mechanisms, with immune cells constantly on patrol, looking for foreign molecules to destroy. So far, it’s been unclear exactly what the mechanism is that allows some particles to pass through the lungs while others are caught and destroyed. Understanding that could help researchers design more effective drugs, and it could provide a better understanding of environmental pollutants.
Tsuda teamed up with imaging expert John Frangioni of Harvard Medical School, who designed the imaging system used to track the nanoparticles. Hak Soo Choi, an instructor of medicine at Harvard Medical School, helped design a number of quantum-dot nanoparticles—tiny, semiconducting crystals—and systematically altered their size, shape, and surface charge. They attached a fluorescent probe to each nanoparticle to make it glow through the body when viewed using the near-infrared imaging device.
Pelham Plastics, a medical-device manufacturer based in New Hampshire, developed a custom-made catheter to deliver the nanoparticles into a rat lung. The catheter enabled the researchers to inject nanoparticles directly into the lung, while at the same time ventilating the lung to simulate breathing.
The team tracked the flow of nanoparticles in real time, up to an hour after injection. Tsuda found that size was the most important determinant for passing through the lungs, followed by a nanoparticle’s surface charge. Particles that were smaller than six nanometers and dipolar (both positively and negatively charged) traveled from the lungs to the lymph nodes and into the bloodstream within just a few minutes. These same particles lit up in the kidneys shortly afterward, implying that they could easily be expelled from the body. The findings are published in the latest issue of the journal Nature Biotechnology.
David Edwards, Gordon McKay Professor of the practice of biomedical engineering at Harvard University, sees the group’s findings as a starting blueprint for designing effective vaccines, which are often targeted to the immune cells in lymph nodes. Edwards says their results may provide a molecular explanation for the success of certain vaccines, such as the hepatitis B vaccine, which is made up of molecules within the range of six to 34 nanometers. “This suddenly just clarifies this issue of what exactly is getting into the lymph system and what is possibly getting into the bloodstream,” he says.
“This work paves the way for new therapeutic approaches for not only local delivery to the lungs but also for systemic delivery via pulmonary administration,” says Joseph DeSimone, director of nanomedicine at the University of North Carolina at Chapel Hill.
In the future, Tsuda and his colleagues plan to do similar studies to evaluate nanoparticle behavior from nasal cavities to the brain. They hope to define similar guidelines by which drugs can be designed and administered intranasally to treat neurological disorders.
“It would be interesting to use their approach to explore issues and opportunities for crossing the blood-brain barrier via intranasal administration,” DeSimone says.