Large-ish nanotech breaks barriers in drug delivery


By John Carroll

A team of researchers at Johns Hopkins University has demonstrated a new way to slip drug-bearing nanoparticles through the body’s protective shields of mucus while surprising even themselves with just how big these microscopic delivery vehicles can be constructed.

By developing nanoparticles designed to mimic the appearance of viruses, they have opened up an appealing commercial opportunity for either licensing the technology to drug developers (who are eager to attack specific disease sites with more-effective therapies) or developing new therapies themselves. And previous research has proven that the nanoparticle pathway can be used to carry a large payload of sustained-release therapeutics.

“We actually thought that 500 nanometers would be so big that there was no way that it would go through,” says Justin Hanes, the associate professor of chemical and biomolecular engineering who supervised the team’s research project. “Based on the existing estimates of the mesh size of human mucus, we thought the largest particle that would go through would be at most a couple of hundred nanometers.”

Samuel K. Lai, a chemical and biomolecular engineering doctoral student at Johns Hopkins, was the lead author of the report, which appeared in the online edition of the Proceedings of the National Academy of Sciences on January 23.

Their work adds to the potential of nanomedicine in fighting disease, a subject that has attracted the attention of a variety of research groups around the globe. In fact, just earlier this year, researchers at Rice University announced that they had redesigned the Buckyball to include nontoxic peptides, giving it the appearance of a virus so that it could deliver medicine inside a cell.

Challenges and discoveries

The Johns Hopkins’ group started with an important insight from Richard Cone, a professor in the university’s department of biophysics, and co-workers. “Cone and his colleagues showed that a few of these small viruses could move in human mucus as fast as in water,” says Hanes.

To the eye, mucus appears to be a slimy, nonporous tissue. But using a high-powered microscope, the tissue comes into focus as a mesh. If you make the delivery vehicle small enough and build it to avoid sticking to the mucus, Hanes says, it can effortlessly slip through the sticky barrier used to trap pathogens and other material before they can harm the host.

A loose analogy is that it’s like someone jumping on a trampoline, he adds. A person is too large to go through, but if you put sand on the net instead it will sift through as you jump on it. “In nature the thing that jiggles nanoparticles is thermal energy. The big difference is that mucus is not just a physical barrier-it is also sticky. So particles small enough to fit through the mesh still get stuck in mucus unless they have special coatings.

Johns Hopkins’ associate professor Justin Hanes (left) supervised the research, while doctoral student Samuel K. Lai served as lead author for the report. The team used nanoparticles to get past the body’s protective shields.
Click here to enlarge image

“We started to see that particles coated with low molecular weight polyethylene glycol-PEG-move extremely fast in mucus,” adds Hanes. What was startling, he says, is that the larger 200 nanometer particles traveled even faster than the 100 nanometer particles. So they asked themselves a new question: Just how big could they make a nanoparticle and still have it slip through mucus?

Viruses that are capable of moving through mucus have surfaces that are densely coated with positive and negative charges, the scientist explains, but the surfaces are net-neutral, meaning that they don’t stick electrostatically. The coating with charged groups also makes the viral surface water-loving, meaning they do not stick by oily interactions. “PEG was shown to be mucus-adhesive,” says Hanes, “but the studies that showed this focused on high molecular weight PEG-the adhesion effect was thought due to the ability of PEG molecules to attach to mucus in a kind of Velcro-like fashion. We thought that coating particles with low molecular weight PEG would prevent any oily interaction between the particle and mucus and make the charge on the nanoparticle net neutral as well.”

The key was using PEG with a molecular weight high enough so that it wasn’t toxic-a well-known process in the drug development field-but not so high that it would stick to the mucus.

Important implications

Hanes is still a little amazed that it worked for the largest particles. He’s even more amazed by the implications. “The advantage is that a larger particle is able to provide a much more sustained release of a wide variety of therapeutic and diagnostic agents,” says Hanes, who is also the director of therapeutics for the Institute for NanoBioTechnology at Johns Hopkins. “The time it takes for drugs to be released from the particles doesn’t increase linearly as you increase particle size; it’s much more than linear.”

By delivering drugs through nano-particles, drug developers can reformulate existing therapies, extending patent protection on active ingredients with a proven safety profile and making the therapeutic more effective. That can add millions of dollars in revenue, potentially making the difference in turning a successful drug into a blockbuster.

The bigger nanoparticle size also accommodates a wider range of drugs, expanding its commercial applications.

“We would envision that the company that owns this technology could partner with quite a few pharmaceutical companies,” says Hanes. “We could license this to an independent company or more likely found a company based on this technology. A start-up company could develop its own line of drugs and also potentially partner with pharmaceutical companies.”

This technology could work with many chemotherapeutic agents by providing extended-release, or dispatching cancer-fighting drugs directly to the tumor site. Drugs could be directed to the lungs, the gastrointestinal tract and the cervicovaginal tract, and applied against a host of big diseases such as chronic obstructive pulmonary disorder, Cystic Fibrosis, Crohn’s disease, inflammatory bowel disease, chronic infections, and more.

Another whole class of drugs could be developed in delivering antibodies through mucosal sites such as the female reproductive tract “where you’re susceptible to infection from viruses. Think about a long-acting treatment to prevent sexually transmitted diseases or viral infection, anthrax, or this year’s flu. You can envision a lot of potential applications of the technology.”

Big, fast and commercial

For now, the researchers are back at pushing the envelope on this nanoparticle breakthrough. They want to see just how big they can make the particle without slowing its passage through mucus. And Hanes and his colleagues, including lead author Dr. Jie Fu, have recently reported on a PEG-coated biodegradable polymer particle version that can encapsulate and deliver a wide array of drug molecules. They have a patent covering the new material and a few patents pending related to the most recent findings reported in PNAS.

“We hope to get 1,000 nanometer particles moving fast,” he says.

Hanes can also envision founding a company that will explore the field even further.

“I’m not leaving Johns Hopkins,” says the researcher, but there’s a distinct commercial opportunity here.

“There are a lot of different avenues to go down on this.”