MIT researchers designed these particles that can produce proteins when ultraviolet light is shone on them. In this case, the protein is green fluorescent protein. Image: Avi Schroeder |
Drugs
made of protein have shown promise in treating cancer, but they are difficult
to deliver because the body usually breaks down proteins before they reach
their destination.
To
get around that obstacle, a team of Massachusetts Institute of Technology (MIT)
researchers has developed a new type of nanoparticle that can synthesize
proteins on demand. Once these “protein-factory” particles reach their targets,
the researchers can turn on protein synthesis by shining ultraviolet light on
them.
The
particles could be used to deliver small proteins that kill cancer cells, and
eventually larger proteins such as antibodies that trigger the immune system to
destroy tumors, says Avi Schroeder, a postdoctoral researcher in MIT’s David H.
Koch Institute for Integrative Cancer Research and lead author of a paper
appearing in NanoLetters.
“This
is the first proof of concept that you can actually synthesize new compounds
from inert starting materials inside the body,” says Schroeder, who works in
the laboratories of Robert Langer, MIT’s David H. Koch Institute Professor, and
Daniel Anderson, an associate professor of health sciences and technology and
chemical engineering.
Langer
and Anderson are also authors of the paper, along with former Koch Institute
postdoctoral researchers Michael Goldberg, Christian Kastrup, and Christopher Levins
Mimicking nature
The researchers came up with the idea for protein-building particles when
trying to think of new ways to attack metastatic tumors—those that spread from
the original cancer site to other parts of the body. Such metastases cause 90%
of cancer deaths.
They
decided to mimic the protein-manufacturing strategy found in nature. Cells
store their protein-building instructions in DNA, which is then copied into
messenger RNA. That mRNA carries protein blueprints to cell structures called
ribosomes, which read the mRNA and translate it into amino acid sequences.
Amino acids are strung together to form proteins.
“We
wanted to use machinery that has already proven to be very effective. Ribosomes
are used in nature, and they were perfected by nature over billions of years to
be the best machine that can produce protein,” Schroeder says.
The
researchers designed the new nanoparticles to self-assemble from a mixture that
includes lipids—which form the particles’ outer shells—plus a mixture of
ribosomes, amino acids, and the enzymes needed for protein synthesis. Also
included in the mixture are DNA sequences for the desired proteins.
The
DNA is trapped by a chemical compound called DMNPE, which reversibly binds to
it. This compound releases the DNA when exposed to ultraviolet light.
“You
want to be able to trigger it so the system turns on only when you want it to
work,” Schroeder says. “When the particles are hit by light, the DNA is
released from a caging compound and then can enter the cycle of producing the
protein.”
Programmable factories
In this study, particles were programmed to produce either green fluorescent
protein (GFP) or luciferase, both of which are easily detected. Tests in mice
showed that the particles were successfully prompted to produce protein when UV
light shone on them.
Waiting
until the particles reach their destination before activating them could help
prevent side effects from a particularly toxic drug, says James Heath, a
professor of chemistry at the California Institute of Technology. However, more
testing must be done to demonstrate that the particles would reach their
intended destination in humans, and that they can be used to produce therapeutic
proteins, he says.
“There
are lots of details left to be worked out for this to be a viable therapeutic
approach, but it is a really terrific and innovative concept, and it certainly
gets one’s imagination going,” says Heath, who was not part of the research
team.
The
researchers are now working on particles that can synthesize potential cancer
drugs. Some of these proteins are toxic to both cancerous and healthy cells—but
using this delivery method, protein production could be turned on only in the
tumor, avoiding side effects in healthy cells.
The
team is also working on new ways to activate the nanoparticles. Possible
approaches include production triggered by acidity level or other biological
conditions specific to certain body regions or cells.
