Researchers at MIT and Brigham and
Women’s Hospital have shown that they can deliver the cancer drug cisplatin
much more effectively and safely in a form that has been encapsulated in a
nanoparticle targeted to prostate tumor cells and is activated once it reaches
its target.
Using the new particles, the researchers
were able to successfully shrink tumors in mice, using only one-third the
amount of conventional cisplatin needed to achieve the same effect. That could
help reduce cisplatin’s potentially severe side effects, which include kidney
damage and nerve damage.
In 2008, the researchers showed that the
nanoparticles worked in cancer cells grown in a lab dish. Now that the
particles have shown promise in animals, the team hopes to move on to human
tests.
“At each stage, it’s possible there will
be new roadblocks that will come up, but you just keep trying,” says Stephen
Lippard, the Arthur Amos Noyes Professor of Chemistry and a senior author of
the paper, which appears in the Proceedings
of the National Academy of Sciences.
Omid Farokhzad, associate professor at Harvard Medical School
and director of the Laboratory of Nanomedicine and Biomaterials at Brigham and
Women’s Hospital, is also a senior author of the paper. Shanta Dhar, a
postdoctoral associate in Lippard’s lab, and Nagesh Kolishetti, a postdoctoral
associate in Farokhzad’s lab, are co-lead authors.
Better delivery
Cisplatin, which doctors began using to treat cancer in the late 1970s,
destroys cancer cells by cross-linking their DNA, which ultimately triggers
cell death. Despite its adverse side effects, which also include nerve damage
and nausea, about half of all cancer patients receiving chemotherapy are taking
Cisplatin or other platinum drugs.
Another problem with conventional
cisplatin is its relatively short lifetime in the bloodstream. Only about 1% of
the dose given to a patient ever reaches the tumor cells’ DNA, and about half
of it is excreted within an hour of treatment.
To prolong the time in circulation, the
researchers decided to encase a derivative of cisplatin in a hydrophobic
(water-repelling) nanoparticle. First, they modified the drug, which is
normally hydrophilic (water-attracting), with two hexanoic acid units—organic
fragments that repel water. That enabled them to encapsulate the resulting
prodrug—a form that is inactive until it enters a target cell—in a
nanoparticle.
Using this approach, much more of the
drug reaches the tumor, because less of the drug is degraded in the bloodstream.
The researchers found that the nanoparticles circulated in the bloodstream for
about 24 hours, at least 5 times longer than un-encapsulated cisplatin. They
also found that it did not accumulate as much in the kidneys as conventional
cisplatin.
To help the nanoparticles reach their
target, the researchers also coated them with molecules that bind to PSMA
(prostate specific membrane antigen), a protein found on most prostate cancer
cells.
After showing the nanoparticles’
improved durability in the blood, the researchers tested their effectiveness by
treating mice implanted with human prostate tumors. They found that the
nanoparticles reduced tumor size as much as conventional cisplatin over 30
days, but with only 30% of the dose.
“They have very elegantly showed not
just improved efficacy but also decreased toxicity,” says Mansoor Amiji, chair
of pharmaceutical sciences at Northeastern
Univ.’s Bouvé College of
Health Sciences, who was not involved in the research. “With a nanoparticle,
you should be able to get higher doses into the patient, so you can have a much
better therapeutic result and not worry as much about side effects.”
This type of nanoparticle design could
be easily adapted to carry other types of drugs, or even more than one drug at
a time, as the researchers reported in a PNAS paper last October. They could
also be designed to target tumors other than prostate cancer, as long as those
tumors have known receptors that could be targeted. One example is the Her-2
receptor abundant in some types of breast cancer, says Lippard.
The particles tested in this paper are
based on the same design as particles developed by Farokhzad and MIT Institute
Professor Robert Langer that deliver the cancer drug docetaxel. A Phase I
clinical trial to assess those particles began last week, run by BIND
Biosciences.
Additional animal testing is needed
before the cisplatin-carrying particles can go into human clinical trials, says
Farokhzad. “At the end of the day, if the development results are all
promising, then we would hope to put something like this in humans within the
next three years,” he says.
