Jeffrey Karp - New nanodevice defeats drug resistance
Tiny particles embedded in gel can turn off drug-resistance genes, then release cancer drugs.
Anne Trafton | MIT News Office
March 2, 2015
often shrinks tumors at first, but as cancer cells become resistant to
drug treatment, tumors can grow back. A new nanodevice developed by MIT
researchers can help overcome that by first blocking the gene that
confers drug resistance, then launching a new chemotherapy attack
against the disarmed tumors.
The device, which consists of gold nanoparticles embedded in a
hydrogel that can be injected or implanted at a tumor site, could also
be used more broadly to disrupt any gene involved in cancer.
“You can target any genetic marker and deliver a drug, including
those that don’t necessarily involve drug-resistance pathways. It’s a
universal platform for dual therapy,” says Natalie Artzi, a research
scientist at MIT’s Institute for Medical Engineering and Science (IMES),
an assistant professor at Harvard Medical School, and senior author of a
paper describing the device in the Proceedings of the National Academy of Sciences the week of March 2.
To demonstrate the effectiveness of the new approach, Artzi and
colleagues tested it in mice implanted with a type of human breast tumor
known as a triple negative tumor. Such tumors, which lack any of the
three most common breast cancer markers — estrogen receptor,
progesterone receptor, and Her2 — are usually very difficult to treat.
Using the new device to block the gene for multidrug resistant protein 1
(MRP1) and then deliver the chemotherapy drug 5-fluorouracil, the
researchers were able to shrink tumors by 90 percent in two weeks.
MRP1 is one of many genes that can help tumor cells become resistant
to chemotherapy. MRP1 codes for a protein that acts as a pump,
eliminating cancer drugs from tumor cells and rendering them
ineffective. This pump acts on several drugs other than 5-fluorouracil,
including the commonly used cancer drug doxorubicin.
“Drug resistance is a huge hurdle in cancer therapy and the reason
why chemotherapy, in many cases, is not very effective”, says João
Conde, an IMES postdoc and lead author of the PNAS paper.
To overcome this, the researchers created gold nanoparticles coated
with strands of DNA complementary to the sequence of MRP1 messenger RNA —
the snippet of genetic material that carries DNA’s instructions to the
rest of the cell.
These strands of DNA, which the researchers call “nanobeacons,” fold
back on themselves to form a closed hairpin structure. However, when the
DNA encounters the correct mRNA sequence inside a cancer cell, it
unfolds and binds to the mRNA, preventing it from generating more
molecules of the MRP1 protein. As the DNA unfolds, it also releases
molecules of 5-fluorouracil that were embedded in the strand. This drug
then attacks the tumor cell’s DNA, since MRP1 is no longer around to
pump it out of the cell.
“When we silence the gene, the cell is no longer resistant to that
drug, so we can deliver the drug that now regains its efficacy,” Conde
When each of these events occurs — sensing the MRP1 protein and
releasing 5-fluorouracil — the device emits fluorescence of different
wavelengths, allowing the researchers to visualize what is happening
inside the cells. Because of this, the particles could also be used for
diagnosis — specifically, determining if a certain cancer-related gene
is activated in tumor cells.
Controlled drug release
The DNA-coated gold nanoparticles are embedded in an adhesive gel
that stays in place and coats the tumor after being implanted. This
local administration of the particles protects them from degradation
that might occur if they were administered throughout the body, and also
enables sustained drug release, Artzi says.
In their mouse studies, the researchers found that the particles
could silence MRP1 for up to two weeks, with continuous drug release
over that time, effectively shrinking tumors.
This approach could be adapted to deliver any kind of drug or gene
therapy targeted to a specific gene involved in cancer, the researchers
say. They are now working on using it to silence a gene that stimulates
gastric tumors to metastasize to the lungs.
“This is an impressive study that harnesses expertise at the
interface of materials science, nanotechnology, biology, and medicine to
enhance the efficacy of traditional chemotherapeutics,” says Jeffrey
Karp, an associate professor of medicine at Harvard Medical School and
Brigham and Women’s Hospital, who was not involved in the research.
“Hopefully this approach will perform in studies beyond 14 days and be
translatable to patients, who are desperate for new and more effective
Graduate student Nuria Oliva is also an author of the paper. The
research was funded by the National Cancer Institute and a Marie Curie
International Outgoing Fellowship.