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