Nanoparticles, in green, targeting bacteria, shown in red. Image: Aleks Radovic-Moreno |
Over
the past several decades, scientists have faced challenges in developing new
antibiotics even as bacteria have become increasingly resistant to existing
drugs. One strategy that might combat such resistance would be to overwhelm
bacterial defenses by using highly targeted nanoparticles to deliver large doses
of existing antibiotics.
In
a step toward that goal, researchers at Massachusetts Institute of Technology (MIT)
and Brigham and Women’s Hospital have developed a nanoparticle designed to
evade the immune system and home in on infection sites, then unleash a focused
antibiotic attack.
This
approach would mitigate the side effects of some antibiotics and protect the
beneficial bacteria that normally live inside our bodies, says Aleks
Radovic-Moreno, an MIT graduate student and lead author of a paper describing
the particles in ACS Nano.
Institute
Professor Robert Langer of MIT and Omid Farokzhad, director of the Laboratory
of Nanomedicine and Biomaterials at Brigham and Women’s Hospital, are senior
authors of the paper. Timothy Lu, an assistant professor of electrical
engineering and computer science, and MIT undergraduates Vlad Puscasu and
Christopher Yoon also contributed to the research.
Rules of attraction
The team created the new nanoparticles from a polymer capped with polyethylene
glycol (PEG), which is commonly used for drug delivery because it is nontoxic
and can help nanoparticles travel through the bloodstream by evading detection
by the immune system.
Their
next step was to induce the particles to specifically target bacteria.
Researchers have previously tried to target particles to bacteria by giving
them a positive charge, which attracts them to bacteria’s negatively charged
cell walls. However, the immune system tends to clear positively charged
nanoparticles from the body before they can encounter bacteria.
To
overcome this, the researchers designed antibiotic-carrying nanoparticles that
can switch their charge depending on their environment. While they circulate in
the bloodstream, the particles have a slight negative charge. However, when
they encounter an infection site, the particles gain a positive charge,
allowing them to tightly bind to bacteria and release their drug payload.
This
switch is provoked by the slightly acidic environment surrounding bacteria.
Infection sites can be slightly more acidic than normal body tissue if
disease-causing bacteria are reproducing rapidly, depleting oxygen. Lack of
oxygen triggers a change in bacterial metabolism, leading them to produce
organic acids. The body’s immune cells also contribute: Cells called
neutrophils produce acids as they try to consume the bacteria.
Just
below the outer PEG layer, the nanoparticles contain a pH-sensitive layer made
of long chains of the amino acid histidine. As pH drops from 7 to 6—representing
an increase in acidity—the polyhistidine molecule tends to gain protons, giving
the molecule a positive charge.
Overwhelming force
Once the nanoparticles bind to bacteria, they begin releasing their drug
payload, which is embedded in the core of the particle. In this study, the
researchers designed the particles to deliver vancomycin, used to treat
drug-resistant infections, but the particles could be modified to deliver other
antibiotics or combinations of drugs.
Many
antibiotics lose their effectiveness as acidity increases, but the researchers
found that antibiotics carried by nanoparticles retained their potency better
than traditional antibiotics in an acidic environment.
The
current version of the nanoparticles releases its drug payload over one to two
days. “You don’t want just a short burst of drug, because bacteria can recover
once the drug is gone. You want an extended release of drug so that bacteria
are constantly being hit with high quantities of drug until they’ve been eradicated,” Radovic-Moreno says.
Although
further development is needed, the researchers hope the high doses delivered by
their particles could eventually help overcome bacterial resistance. “When
bacteria are drug resistant, it doesn’t mean they stop responding, it means
they respond but only at higher concentrations. And the reason you can’t
achieve these clinically is because antibiotics are sometimes toxic, or they
don’t stay at that site of infection long enough,” Radovic-Moreno says.
One
possible challenge: There are also negatively charged tissue cells and proteins
at infection sites that can compete with bacteria in binding to nanoparticles
and potentially block them from binding to bacteria. The researchers are
studying how much this might limit the effectiveness of their nanoparticle
delivery. They are also conducting studies in animals to determine whether the
particles will remain pH-sensitive in the body and circulate for long enough to
reach their targets.
