Nanoparticle theories slowly turn into practice

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Nanoparticle Theories
Slowly Turn into Practice
• Putting together interdisciplinary teams: “Biologists,
chemists, clinicians, material scientists, and engineers
are not going to talk the same language on day one,” says
Piotr Grodzinski, PhD, director of the National Cancer
Institute’s Office of Cancer Nanotechnology Research.
Why has nanotech drug delivery taken so long to
“You need to create a collaborative environment for large
reach the clinic?
projects in which they are empowered to work together.”
This recognition helped to produce the National
Start with small interfering RNA (siRNA) molecules that
Cancer Institute’s Centers of Cancer Nanotechnology
attack messenger RNAs for ribonucleotide reductase, a cliniExcellence, each led by one researcher with a medical
cally validated target for aggressive cancers not responding
background and another with a technical background.
to therapy. Wrap up the siRNAs in a cunningly designed
“You couldn’t do this kind of research with a single
polymer nanoparticle and plop hydrophilic shields
lab,” says Sanjiv Sam Gambhir, MD, PhD, direcand targeting agents on the outside. Less than 100
tor of Stanford University’s Center for Cancer
nm in diameter, the nanoparticle is designed
Nanotechnology Excellence and Translation.
to bypass the difficulties in systemically dis“And it takes several years for people to really
tributing siRNAs and to accumulate with its
start working well together.”
peers by binding to a transferrin receptor on
On the upside, “the collaborative envithe surface of a tumor cell, where it is swalronment has improved tremendously,” says
lowed by endocytosis and releases its active
James R. Baker Jr, MD, of the University
ingredient.
of Michigan, director of the Michigan
This is Calando Pharmaceuticals’
Calando Pharmaceuticals
Nanotechnology Institute for
CALAA-01 drug, based on research
Special delivery: The CALAA-01 drug from Calando
Medicine and Biological Sciences.
by Mark E. Davis, PhD, at Caltech,
Pharmaceuticals, now in clinical trials, packages siRNAs
This improvement is particularly
whose lab began clinical tests in
into a nanoparticle < 100 nm in diameter with stabilizing
noticeable in young researchers,
and targeting molecules on the outside.
2008 for patients with treatmentwho “innately cross-train,” he says.
resistant solid tumors. Early proof• Mastering highly complex approaches: Calando’s
of-concept data published last year in Nature (Nature 2010;
CALAA-01 needs all its components working optimally
464:1067–70) showed that the nanoparticles do move to tutogether to unleash its effect on a tumor, says Thomas
mors, where they apparently cut mRNAs as planned and are
Schluep, ScD, the firm’s chief scientific officer. “That
tolerated reasonably well. The trial will wrap up early next year.
made it very difficult to develop.”
In January, BIND Biosciences kicked off phase I trials for
its BIND-014 nanoparticle in patients with advanced or met• Scaling up manufacturing: “There are thousands of publications about nanoparticles,” says Scott Minick, MBA,
astatic cancer to establish the maximum tolerated dose and
BIND Biosciences chief executive officer. “Practically speakpharmacokinetics. BIND-014 contains docetaxel, the active
ing, the vast majority of these nanoparticle technologies,
ingredient in Taxotere from Sanofi-Aventis. The company
maybe as much as 99%, are not clinically viable or translatsays that in preclinical models it delivered up to 20 times
able to commercial-scale pharmaceutical manufacturing.”
more docetaxel to the tumor site than an equivalent dose of
However, many companies are starting to scale up manuinfused Taxotere, with greater efficacy and less severe side effacturing, producing hundreds of grams or even kilograms,
fects. The nanoparticle seeks out prostate-specific membrane
Grodzinski notes.
antigen (PSMA), which is strongly expressed on blood vessels
in solid tumors and on the surface of certain cancer cells.
Seeing startups
Another offshoot from the Davis lab is being studied in
Proponents can point to definite signs of progress. Among
a 150-patient phase II clinical study for the treatment of
them,
the U.S. Food and Drug Administration has approved
advanced non–small cell lung cancer. Cerulean Pharma’s
a few nanotech-based therapies, including Abraxane (pacliCRLX101 nanopharmaceutical contains camptothecin,
taxel; Celgene), Doxil (doxorubicin; Johnson & Johnson), and
which inhibits both topoisomerase 1 and hypoxia-inducible
Oncaspar (pegaspargase; Sigma-Tau).
factor-1α. CRLX101 is sized to exploit the porosity of tumor
The number of clinical trials is rising, and so is the numvasculature, “which creates a beautiful entry portal,” says
ber of startups in nanotech medicine, which Grodzinski esCerulean chief executive officer Oliver S. Fetzer, PhD. In
timates at 35 to 40 firms in the United States in the past few
earlier trials, he says, patients have commented on how good
years. Although all of these firms are small, “linking them
they feel, compared to their experiences with other drugs.
strategically to larger pharmaceutical companies will further
But although the last decade has seen an unending flood
improve their chances to succeed and commercialize their
of striking ideas for nanotechnology-based delivery for cantechnologies,” he says.
cer agents, these 3 drugs are among very few in clinical trials.
“This is still a really young field,” says Schluep. “We are truly
Making particle progress
pioneers in that we are quite far along in our clinical development with an ongoing clinical trial, which is no small feat.
Here, researchers say, are some of the challenges in nanoLook at the timeline for developing monoclonal antibodies—
tech medicine that go beyond those of conventional drug
that didn’t happen overnight either.” —Eric Bender
development:
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Nanoparticle Theories Slowly Turn into Practice
Cancer Discovery 2011;1:280.
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