W. Mark Saltzman has been trying to cure brain tumors for decades. Time after time, he hit a common roadblock: A delivery device that works is too toxic, but a good treatment doesn’t work if it’s not in the right place.
It’s a kind of Holy Grail for the people who have made fighting cancer their life’s work—getting potentially life-saving treatment to the part of the brain where it’s most likely to save a patient.
Now, Saltzman (pictured), a Yale professor, and his colleagues may have found a way to hit the sweet spot, using an ultra-tiny tool as their chief weapon: a new nanoparticle that could have benefits for treating a variety of diseases.
Potentially, Saltzman said, therapeutic nanoparticles—a nanometer is a billionth of a meter—could be injected directly into the brain through catheters, then steered to just the right place using varying pressure. That means hurdling the barrier between the bloodstream and the brain, an impediment to many treatments for brain cancer. Once delivered, the drug would continue to release the drug to do its cancer-killing work.
“We’re optimistic that this is going to be a much better approach,” said Saltzman, the Goizueta Foundation professor of biomedical engineering and chemical and environmental engineering at Yale’s School of Engineering & Applied Science. He’s also the chair of the biomedical engineering department.
Saltzman and his colleagues published a paper outlining the new nanoparticle formula late last year; he said recently that additional work looking at its effectiveness on brain cancer is ongoing.
The Gold Rush
Nano-enabled applications are exploding in the medical world, perhaps nowhere more than in the fight against cancer.
It’s not just ultra-effective, targeted treatments, but a whole range of innovations that could usher in the long-promised era of dominance over a host of debilitating, or lethal, diseases. Super fast diagnostic tests, now in development, could tell you what strain of cancer you have, or tell the difference between a benign and malignant tumor, without surgery or an invasive test.
Researchers like Saltzman see nanotechnology as a way to give patients a better prognosis while minimizing the well-known toxic side effects associated with more established chemotherapy and radiation treatments.
Potential breakthroughs like this one were inconceivable 30 years ago, before scientists began unlocking the potential of therapies using individual genes to concoct cures—and started looking to the promise of nanotechnology for better ways to zap cancer cells.
The list of treatments in development is long. Researchers are heating nano-gold shells to target, and torch, tumors. They’re using super-small iron oxide and titanium dioxide to override ovarian cancer cells’ resistance to chemotherapy.
Tiny silica particles that light up, known as “Cornell dots” for the university where they were developed, are shaping up as crack cancer detectors—and have moved into the clinical-trial phase.
Only a few nano-type drugs are on the market; a larger set are in the testing stage. But inside laboratories at universities and pharmaceutical companies, the science of the very small is a big deal when it comes to stopping cancer.
As with all efforts that tap into nanotechnology, however, there are potential drawbacks. The interesting properties of these super-small materials sometimes raise other questions. Among them are whether some materials, such as nano-sized gold, can be eliminated from the body without doing any damage.
“My understanding is that the biggest hurdle is actually the clearance of these particles,” said Ming Su, a professor at the University of Central Florida, who’s associated with the school’s NanoScience Technology Center. Su has been working on using nanomaterials for cancer detection, as well as on the toxicity of a number of ultra-tiny substances.
“It’s really hard to estimate the long-term effect of particles in your body,” he said. “People have only been doing this for a few years.”
FDA & Nano
Nanomaterials are increasingly common in both research laboratories and everyday products, turning up in everything from sunscreens to stain-repellent pants. In many of these workaday applications, nano-enabled products face little, if any, scrutiny from the federal government, although there are signs that may be changing.
In medical treatments, however, nanotechnology is as carefully controlled as any drug. The U.S. Food and Drug Administration has a lengthy process just for allowing new therapies to be tested on people, let alone approved for widespread use.
The FDA has said it considers any drug or treatment that uses nanotechnology to be a new drug, which subjects a therapy to the tightest controls. Regardless of the ongoing argument over whether the FDA’s process is the most efficient way to bring new drugs to the market, there’s no question that nano-enabled therapies will be vetted before they hit your doctor’s prescription pad—something that can’t be said about a number of other products that use nanomaterials.
Given that anticipated scrutiny, toxic consequences are on the mind of nanomedical researchers. Part of that is built into their everyday mindset; after all, drugs and treatments that hurt people generally aren’t approved, and if they are, subsequent problems are literally fatal.
The possibility of side effects or long-term fallout has particular resonance for cancer research, because the existing treatments take such a toll on patients. Researchers see themselves as having a dual role: To find treatments that are not just better, but less debilitating.
Gene Therapy: Promise, With A Price
Another project that Saltzman and his colleagues are working on aims squarely at that goal. It involves making gene therapy—a hot topic in biomedicine, with potential to help curtail a number of diseases—easier to use. Gene therapy revolves around DNA, using the very strands of life to improve treatments, often by correcting the mutations that make people sick, or by killing a cell that’s causing problems like cancer.
“There are lots of ways to try to deliver genes to cells. Almost all of them are toxic,” Saltzman said. “The challenge is to deliver with the least amount of toxicity.”
That has been a key challenge of gene therapy: Making polymers to deliver the DNA without making it dangerous. That means resolving imbalances in electrical charge; DNA carries a negative charge, while most polymers are positively charged. Too much positive charge, and the treatment is poisonous.
Salzman and his colleagues tried to design polymers that strike a better balance, making their polymer more water-repellent and creating a more balanced—and less toxic—substance. A better delivery, he said, may open doors treating a variety of diseases, from cancer to cystic fibrosis.
The team uses polyester-based polymers, which dissolve fairly easily.
“Because of water, they slowly degrade, which the body can clear,” Salzman said. “We intentionally design our polymers so that they disappear.”
And, in the process, solves the toxicity problems on both ends.
At this point, Saltzman said, the race to build a better delivery system is on par with the effort to find better treatments.
“I think it’s both,” he said. “Certainly, our focus has been if you can’t get the agent to the cells you can’t do anything. At the same time, we’re trying to identify the best kind of agents.”
That’s where the interdisciplinary nature of the nanomedical field is most useful, at Yale and around the world. Uniting medical researchers and engineers allows cross-pollination of ideas, so that a novel drug and a new way to get it into the body can be developed in concert.
Meanwhile, nanotechnology researchers are also chasing better diagnostic tools and medical devices that leverage tiny materials for big gains.
Qun Huo, pictured, a professor with UCF’s nano center, is zeroing in on gold nanoparticles to spot cancer cells and do other analysis. The technique she’s developing basically monitors the changes in size, or an increase in clustering, of the nanoparticles as they’re exposed to the cells being tested.
Nanomedicine is still in its infancy, she said, but has great potential to transform the diagnostic field.
Instead of waiting days or weeks for a test result, nano-enabled sensors or diagnostic tools might give you an answer in minutes. Some use magnetic nanoparticles to improve existing imaging tools, perhaps finding smaller tumors much sooner. Others use sensors to detect cancer, like a nano-based “nose” that can detect lung cancer in a patients breath.
These types of developments are not only faster, but they could also enable patients to skip biopsies or surgeries just to find out what’s going on inside their bodies.
“It allows them to see what they could not see before and do what they could not do before,” Huo said. “When it comes to cancer diagnosis, it may not be me, but I do actually believe with the technology we have that we can really bring breakthroughs.”
Development: Risk Vs. Reward
Of course, all the potential in the world won’t help bring these treatments, tests and devices to the marketplace. The crucial first step in developing a new treatment is money.
Many of these new ideas are coming from pharmaceutical companies. Others are germinating within the academic community, sometimes with federal funding, sometimes with money from drug companies. At the university level, however, there’s tension between teaching, research and the long and sometimes arduous path to commercializing a laboratory discovery.
The federal government is funding lots of research. For example, the National Cancer Institute, part of the National Institutes of Health, has its own Alliance for Nanotechnology in Cancer, which aims to push innovation as well as keep an eye on questions about impacts on health and the environment.
The NCI has established Centers of Cancer Nanotechnology Excellence to foster research, and also funds the Nanotechnology Characterization Laboratory, which supports researchers with critical work on safety.
Most big research universities, including Yale, have divisions that handle finding investors and selling off patents and ideas. Huo took another route, starting her own spinoff company, Nano Discovery Inc., and has hired staff to deal with the tasks she doesn’t have time for.
But while academics are rewarded for home-run research, actually bringing a therapy to market doesn’t have much currency inside a university setting.
“If the university wants faculty to succeed in commerce, then you do have to concede that faculty have to spend time doing this,” Huo said.
The Evolution Of A Cancer Fighter
Saltzman is familiar with the difficulties of navigating the science, the testing and the successes and failures of new treatments. He started working in Gliadel, a chemo-coated wafer that’s implanted directly into the brain of a cancer patient, in 1988, while at Johns Hopkins University. FDA approval came in 1996—a relatively fast track to the market.
But Gliadel, while helpful to many, wasn’t the magic bullet. More than 20 years later, Saltzman is still trying to find the panacea. His optimism is stronger than ever, he said, because of the way scientists are able to manipulate cells, genes and particles—pushing the envelope in new ways almost every day.
“I’m very confident that once we work out the delivery system ... I think we’ll quickly get to things that are better,” he said. “These kinds of tools have really changed what we can think about doing.”