Effective treatment of cancer requires getting the drugs precisely to the target. Enter the nanoparticle.
When Mary Davis nearly died from the drug used to treat her breast cancer, she issued a challenge to her scientist husband: would he switch his research focus to the design of better cancer treatments? As a chemical engineer at the California Institute of Technology in Pasadena, Mark Davis was creating solid catalysts for use in chemical synthesis. But in 1996, after Mary's experience with the highly toxic chemotherapy drug doxorubicin — dubbed the 'red death' — he heeded her plea and went to work.
Davis used his engineering know-how to design an armour-like particle less than one-thousandth the width of a human hair to encase the drug camptothecin. About ten years after his wife's treatment, he watched doctors inject this molecule, now called CRLX101, into the first patient, Ray Natha. “It was the scariest thing I've ever done,” Davis recalls. During the six-month safety trial, Natha's pancreatic cancer, which had spread to his lungs, stalled. And the nanoparticle-coated drug seemed to cause fewer side effects than did unprotected drugs.
Building protective coats around toxic molecules could address one of cancer treatment's biggest remaining challenges — how to spare healthy cells when attacking cancerous ones. Chemotherapy drugs kill rapidly dividing cells to prevent the rampant cell growth that results in tumours. But these drugs reach cancer cells through the same network of blood vessels that supplies the whole body. And, as Mary Davis's experience shows, they are just as likely to poison healthy cells as cancerous ones.
Researchers are therefore working on ways to deliver drugs directly to cancerous tissue. Drug delivery is a multi-stage journey: the active agent needs to enter the body, travel through the bloodstream to arrive at the tumour site, penetrate the tumour mass and then gain entry to the cells (see 'Hole in one'). By refining each step, researchers aim to do more than just protect the body from toxic medication. Pioneering drug-delivery systems are designed to transport payloads — from highly toxic molecules to genetic material — that should never travel through the body alone, and to target cancer cells more precisely than is now possible.
Much of the excitement over developments in cancer therapy has focused on drugs that target cancer-specific biological pathways, says Steven Libutti, a cancer surgeon at the Albert Einstein College of Medicine in New York. “But this method may not deliver the promise that we hoped, because the tumours themselves evade that strategy,” he says. The alternative is to use potent drugs that are toxic to all cells, but to corral these in a benign 'Trojan horse' until they reach the tumour, he says.
One of the simplest ways to do this is to arm cancer-seeking proteins with a cell-killing drug. In the late 1990s, drug companies developed antibodies that bind to the surface of certain types of cancer cell. Fusing these proteins to drugs with a stable chemical linker yields a potent combination: the antibodies encourage uptake of the drug into cancer cells and the linker keeps the drug from working until it gets inside. “It's a simple idea,” says John Lambert, chief scientific officer at ImmunoGen in Waltham, Massachusetts, which develops and licenses the technology that links the antibody to the drug. “But it has taken a long time to put all the pieces together.”
Only two antibody–drug conjugate (ADC) therapies are on the market. The first, called brentuximab vedotin (marketed by Seattle Genetics in Washington as Adcetris), was approved by the US Food and Drug Administration (FDA) in 2011 to treat some types of lymphoma, cancers of the lymph system, that had not responded to previous treatment. The second, trastuzumab emtansine (marketed by Genentech of South San Francisco, California, as Kadcycla), was approved in 2013 as a treatment for late-stage breast cancer after treatment with conventional chemotherapeutics.
Trastuzumab emtansine fuses emtansine, a toxic chemotherapeutic, to antibodies that bind to a protein receptor called HER2, which is overproduced by about 20% of breast cancers. In a phase III trial that finished in 2012, the nearly 500 women who took the drug lived about five months longer and had fewer side effects than did those on the standard treatment1. All women in the study were in advanced stages of the disease, but the drug is now in clinical testing as a first-line treatment thanks to the positive results from the trial, says Lambert. Several similar drugs are now in advanced clinical trials, and ImmunoGen is trying to link emtansine to antibodies that target other cancers, from lymphoma to lung and ovarian cancers.
Like conventional monoclonal antibodies, ADCs need to make their own way to the tumour site. “The molecules you inject have no idea where the cancer cell is,” says Lambert. “If they pass by the cancer cell they can attach, but most go elsewhere.”
One approach is to add a coat around chemotherapy drugs. The resulting nanoparticles, which range from about 20 to 100 nanometres in diameter, are too large to escape most blood vessels. But they do find their way out of the leakier ones hastily built by a rapidly growing tumour. As a result, they are thought to accumulate preferentially at the tumour site. However, this phenomenon has been studied mostly in animal models and not in people, says Rudolph Juliano, a pharmacologist at the University of North Carolina at Chapel Hill.
Nanoparticles can carry a stronger payload than can antibodies, encasing thousands of drugs in a single molecule. Unfortunately, however, they can also accumulate in the liver and the spleen, where they provide no therapeutic benefit and can cause side effects. To minimize unwanted effects, researchers coat the particles with a layer of polyethylene glycol, which mimics water and effectively hides the drug from the liver cells that detect and engulf intruders. But minimizing liver uptake is still an important part of nanoparticle design, says Juliano.
The first nanoparticles to be developed for drug delivery coated the active agent with lipids. The first drug of this type to be approved was Doxil, in 1995. Doxil carries doxorubicin and is used to treat Kaposi's sarcoma and other solid tumours, including breast and ovarian cancer.
According to the US National Cancer Institute, six such nanoparticles are currently approved for use on the market worldwide. So far, they seem to improve safety — Doxil does not end up in the heart, where doxorubicin causes toxicity — but not efficacy. As a result, some researchers have questioned whether nanotechnology is worth the high price tag that accompanies its production: it can cost ten times more than conventional treatment. “New nanoparticle-based drug delivery will be expensive and it has to be justified by improved therapeutic outcomes,” says Juliano. “We're still at too early a stage to ascertain that.”
Still, nanoparticle drug delivery can have a dramatic and worthwhile effect, says Yun Yen, an oncologist at the City of Hope cancer centre in Duarte, California, who administered CRLX101 (developed by Cerulean Pharma in Cambridge, Massachusetts) to Natha. “It's quite amazing when you see a patient and you're expecting their blood count to drop and you're expecting them to be nauseous, but they do so well,” he says.
Engineered for delivery
Nanotechnology has yet to achieve its full potential because it has so far been used only to ferry drugs intended to be administered through conventional methods, says Omid Farokhzad, a physician-scientist at Harvard Medical School in Boston, Massachusetts, and founder of three nanotechnology-based biotech companies in Massachusetts. One of Farokhzad's companies, Blend Therapeutics in Watertown, is working to engineer drugs specifically for use in nanoparticles.
Farokhzad's other two companies — BIND Therapeutics of Cambridge and Selecta Biosciences of Watertown — use technology that engineers a long polymeric string that spontaneously folds to form a particle. The polymers are interspersed with targeted ligands designed to link the particles to cancer cells. The self-assembly makes it easier for scientists to reproduce the molecule in different batches — a key advantage for translating the technology into the clinic. In a 2012 study, Farokhzad and his colleagues screened 100 polymers that incorporate a molecule that binds to a prostate-specific membrane antigen (PSMA), which is displayed on the surface of most prostate tumours2. The particles enclose a chemotherapeutic, docetaxel. The most promising of the nanoparticles, BIND-014, is in phase II trials for treatment of lung and prostate cancer.
Some researchers are branching out from conventional chemotherapy and using nanoparticles to deliver small pieces of RNA to cancer cells, where they decrease expression of certain genes in a method called RNA interference. Davis says that the use of nanoparticles to deliver RNA is promising because it allows researchers to reach multiple genes, and thus pathways, in one hit. He developed the first RNA-carrying nanoparticle to enter clinical trials for cancer. The particle, called CALAA-01, targets the gene RRM2, which is involved in cell division and uses molecules that bind to the transferrin receptor, which is highly expressed on cancer cells, to gain access to the cell interior3. CALAA-01 entered phase I clinical trials to treat melanoma, but the follow-up trial was halted for reasons that have not been made clear.
We've built a truck and we have a GPS system. You can load anything on the truck.
Other efforts aim to bring drugs directly to the tumour. Sylvain Martel, a biomedical engineer at Montreal Polytechnic in Canada, is building magnetic particles that researchers will be able to guide to the tumour. These particles use the same contrast agent as in magnetic resonance imaging (MRI), so when a patient is in an MRI scanner researchers can use a strong magnetic field on top of the tumour to guide drugs to the correct site. Martel and his colleagues have tested the method in pigs and aim to try it in people. The magnetic particles can enclose other targeting particles, Martel says. “We've built a truck and we have a GPS system,” he says. “You can load anything into the truck.”
This vision of a researcher driving a drug directly to the site of a tumour is far from the whole-body onslaught that Mary Davis experienced nearly 20 years ago. Today, the drug she encouraged her husband to develop is nearing the end of phase II clinical trials and has been used to treat hundreds of patients. Future therapies may strike even more efficiently, with fewer side effects, says Mark Davis. “We need to think about ways of driving down cancer so people can have a reasonable life without all the added side effects and toxicities.”
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Hrkach, J. et al. Sci. Transl. Med. 4, 128ra39 (2012).
Davis, M. E. et al. Nature 464, 1067–1070 (2010).
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Wright, J. Nanotechnology: Deliver on a promise. Nature 509, S58–S59 (2014). https://doi.org/10.1038/509S58a
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