The layers of mucus that protect sensitive tissue
throughout the body have an undesirable side effect: They
also can keep helpful medications away. To overcome this
hurdle, Johns Hopkins researchers have found a way to coat
nanoparticles with a chemical that helps them slip through
this sticky barrier.
During experiments with these coated particles, the
researchers also discovered that mucus layers have much
larger pores than previously thought, providing a doorway
that should allow larger and longer-acting doses of
medicine to reach the protected tissue.
The team's findings were reported last week in the
online Early Edition of Proceedings of the National
Academy of Sciences.
The discoveries are important because mucus layers,
which trap and help remove pathogens and other foreign
materials, can block the localized delivery of drugs to
many parts of the body, including the lungs, eyes,
digestive tract and female reproductive system. Because of
these barriers, doctors often must prescribe pills or
injections that send drugs through the entire body, an
approach that can lead to unwanted side effects or doses
that are too weak to provide effective treatment.
"Mucus barriers evolved to serve a helpful purpose: to
keep things out," said Justin Hanes, an associate professor
of chemical and
biomolecular engineering in the Whiting School, who
supervised the research. "But if you want to deliver
medicine in a microscopic particle, they can also keep the
drugs from getting through. We've found a way to keep
helpful nanoparticles from sticking to mucus, and we
learned that the openings in the mucus 'mesh' are much
larger than most people expected. These findings set the
stage for a new generation of nanomedicines that can be
delivered directly to the affected areas."
To get its particles past the mucus, Hanes' team
studied an unlikely model: viruses. Earlier research led by
Richard Cone, a professor in the
Department of
Biophysics in the Krieger School of Arts and Sciences,
had established that some viruses are able to make their
way through the human mucus barrier. Hanes and his
colleagues decided to look for a chemical coating that
might mimic the characteristics of a virus.
Samuel K. Lai, lead author of the journal article and
a chemical and biomolecular engineering doctoral student,
said, "We found that the viruses that got through had
surfaces that were attracted to water, and they had a net
neutral electrical charge. We thought that if we could coat
a drug-delivery nanoparticle with a chemical that had these
characteristics, it might not get stuck in the mucus
barrier."
To make their nanoparticles behave like viruses, the
researchers coated them with polyethylene glycol, or PEG, a
nontoxic material commonly used in pharmaceuticals. PEG
dissolves in water and is excreted harmlessly by the
kidneys.
The researchers also considered the size of their
nanoparticles. Previous studies indicated that even if
nanoparticles did not stick to the mucus, they might have
to be smaller than 55 nanometers wide to pass through the
tiny openings in the human mucus mesh. (A human hair is
roughly 80,000 nanometers wide.) Using high-resolution
video microscopy and computer software, the researchers
discovered that their PEG-coated 200-nanometer particles
could slip through a barrier of human mucus.
They then conducted further tests to see how large
their microscopic drug carriers could be before they got
trapped in the mesh. Larger nanoparticles are more
desirable because they can release greater amounts of
medicine over a longer period of time.
Said Hanes, who also serves as director of
therapeutics for the
Institute for NanoBioTechnology at Johns Hopkins, "We
wanted to make the particles as large as possible. The
shocking thing was how fast the particles that were 500
nanometers wide moved through the mucus mesh. The work
suggests that the openings in the mucus barrier are much
larger than originally expected by most. And we were also
surprised to find that the larger nanoparticles (200 and
500 nanometers wide) actually moved through the mucus layer
more quickly than the smaller ones (100 nanometers
wide)."
This has important implications, Hanes said, because a
500-nanometer particle can be used to deliver medicine to a
targeted area, released over periods of days to weeks.
Larger particles also allow a wider array of drug molecules
to be efficiently encapsulated. He and his colleagues
believe this system has great potential in the delivery of
chemotherapy, antibiotics, nucleic acids and other
treatment directly to the lungs, gastrointestinal tract and
cervicovaginal tract.
Through Johns Hopkins Technology Transfer, the team
has applied for patents covering this process.
In addition to Lai, Hanes and Cone, co-authors of the
PNAS paper were D. Elizabeth O'Hanlon and Suzanne Harrold,
doctoral students in the Department of Biophysics in the
Krieger School; Stan T. Man, a former visiting research
scientist in the Department of Chemical and Biomolecular
Engineering in the Whiting School; and Ying-Ying Wang, who
contributed to the research as an undergraduate and who is
now a graduate student in the Department of Biomedical
Engineering.
Lai's participation was partially supported by a
scholarship from the Natural Science and Engineering
Research Council of Canada.