An artist’s rendering of BIND-014. Image: Digizyme Inc.
therapeutic nanoparticles that accumulate in tumors while bypassing healthy
cells have shown promising results in an ongoing clinical trial, according to a
nanoparticles feature a homing molecule that allows them to specifically attack
cancer cells, and are the first such targeted particles to enter human clinical
studies. Originally developed by researchers at Massachusetts Institute of
Technology (MIT) and Brigham and Women’s Hospital in Boston, the particles are designed to carry
the chemotherapy drug docetaxel, used to treat lung, prostate and breast
cancers, among others.
the study, which appears in Science Translational Medicine, the
researchers demonstrate the particles’ ability to target a receptor found on
cancer cells and accumulate at tumor sites. The particles were also shown to be
safe and effective: Many of the patients’ tumors shrank as a result of the
treatment, even when they received lower doses than those usually administered.
initial clinical results of tumor regression even at low doses of the drug
validates our preclinical findings that actively targeted nanoparticles
preferentially accumulate in tumors,” says Robert Langer, the David H. Koch
Institute Professor in MIT’s Department of Chemical Engineering and a senior author
of the paper. “Previous attempts to develop targeted nanoparticles have not
successfully translated into human clinical studies because of the inherent
difficulty of designing and scaling up a particle capable of targeting tumors,
evading the immune system and releasing drugs in a controlled way.”
Phase I clinical trial was performed by researchers at BIND Biosciences, a
company cofounded by Langer and Omid Farokhzad in 2007.
study demonstrates for the first time that it is possible to generate medicines
with both targeted and programmable properties that can concentrate the
therapeutic effect directly at the site of disease, potentially revolutionizing
how complex diseases such as cancer are treated,” says Farokhzad, director of
the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s
Hospital, associate professor of anesthesia at Harvard Medical School and a
senior author of the paper.
at Dana-Farber Cancer Institute, Weill
College, TGen Clinical Research
Services in Phoenix, and the Karmanos Cancer
Institute in Detroit
were also involved in the study.
Langer’s laboratory started working on polymeric nanoparticles in the early
1990s, developing particles made of biodegradable materials. In the early
2000s, Langer and Farokhzad begin collaborating to develop methods to actively
target the particles to molecules found on cancer cells. By 2006 they had
demonstrated that targeted nanoparticles can shrink tumors in mice, paving the
road for the eventual development and evaluation of a targeted nanoparticle
called BIND-014, which entered clinical trials in January 2011.
this study, the researchers coated the nanoparticles with targeting molecules
that recognize a protein called PSMA (prostate-specific membrane antigen),
found abundantly on the surface of most prostate tumor cells as well as many
other types of tumors.
of the challenges in developing effective drug-delivery nanoparticles, Langer
says, is designing them so they can perform two critical functions: Evading the
body’s normal immune response and reaching their intended targets.
need exactly the right combination of these properties, because if they don’t
have the right concentration of targeting molecules, they won’t get to the
cells you want, and if they don’t have the right stealth properties, they’ll
get taken up by macrophages,” says Langer, also a member of the David H. Koch
Institute for Integrative Cancer Research at MIT.
BIND-014 nanoparticles have three components: One that carries the drug, one
that targets PSMA, and one that helps evade macrophages and other immune-system
cells. A few years ago, Langer and Farokhzad developed a way to manipulate
these properties very precisely, creating large collections of diverse
particles that could then be tested for the ideal composition.
systematically made a set of materials that varied in the properties they
thought would matter, and developed a way to screen them. That’s not been done
in this kind of setting before,” says Mark Saltzman, a professor of biomedical
engineering at Yale
University who was not
involved in this study. “They’ve taken the concept from the lab into clinical
trials, which is quite impressive.”
of the particles are made of polymers already approved for medical use by the
U.S. Food and Drug Administration.
The Phase I clinical trial involved 17 patients with advanced or metastatic
tumors who had already gone through traditional chemotherapy. In Phase I
trials, researchers evaluate a potential drug’s safety and study its effects in
the body. To determine safe dosages, patients were given escalating doses of
the nanoparticles. So far, doses of BIND-014 have reached the amount of
docetaxel usually given without nanoparticles, with no new side effects. The
known side effects of docetaxel have also been milder.
the 48 hrs after treatment, the researchers found that docetaxel
concentration in the patients’ blood was 100 times higher with the
nanoparticles as compared to docetaxel administered in its conventional form.
Higher blood concentration of BIND-014 facilitated tumor targeting resulting in
tumor shrinkage in patients, in some cases with doses of BIND-014 that correspond
to as low as 20% of the amount of docetaxel normally given. The nanoparticles
were also effective in cancers in which docetaxel usually has little activity,
including cervical cancer and cancer of the bile ducts.
researchers also found that in animals treated with the nanoparticles, the
concentration of docetaxel in the tumors was up to tenfold higher than in
animals treated with conventional docetaxel injection for the first 24 hrs, and
that nanoparticle treatment resulted in enhanced tumor reduction.
Phase I clinical trial is still ongoing and continued dose escalation is
underway; BIND Biosciences is now planning Phase II trials, which will further
investigate the treatment’s effectiveness in a larger number of patients.
development of the particles at MIT and Brigham and Women’s Hospital was
supported by funding from the National Cancer Institute, the National Institute
of Biomedical Imaging and Bioengineering, the David H. Koch Institute for
Integrative Cancer Research at MIT, the Prostate Cancer Foundation, a gift from
David H. Koch and the Dana-Farber Harvard Cancer Center Prostate Cancer SPORE.
Subsequent development by BIND Biosciences was supported by funding from the
National Cancer Institute, the National Institute of Standards and Technology,
and BIND Biosciences.