Tiny vehicles deliver more medication to tumors and reduce side effects
Cancer plays a deadly game of hide-and-seek in the body, and the drugs sent to treat it are often the losers—as is the cancer patient. The drugs have trouble distinguishing between tumor cells and healthy ones and may drop their payload on the normal cells, causing miserable side effects and leaving nearby cancer cells untouched. Malignancies may also get a helping hand from the body’s own leading defense weapon, the immune system. It often mistakes anticancer drugs for harmful bacteria or other foreign invaders and breaks them down. The shattered pieces are conveyed to the body’s trash receptacles in the liver, kidneys and spleen, again, before they reach their intended target. Even when the drugs do manage to arrive at a tumor, many of them become entangled in the dense undergrowth of the malignant mass—unable to penetrate it completely.
Recent advances in nanomedicine are now allowing drugs to better traverse this fraught landscape and hit tumors where they live. The key is a uniquely crafted drug vehicle, wrapped in a protective outer shell, that shuttles the chemotherapy drugs through the body. Fine-grained control over the components from which the vehicles are built, which can be just a few billionths of a meter across, has let scientists create a specialized architecture that, among other things, does not trip immune system alarms. Researchers such as Kazunori Kataoka of the University of Tokyo and his colleagues have tucked potent chemotherapy drugs inside sheaths the size of a hepatitis C virus— some 200 times as small as a red blood cell. On a molecular level, those drugs look a lot more like something the body makes. These compounds also have the advantage of being able to slip into tumors and steer clear of healthy cells.
Several versions of nanodrug vehicles from Kataoka’s team, each holding different medications and aimed at different types of tumors, are now wending their way through the final stages of clinical trials in Asia. Drugs in these new carriers have slowed or reversed disease progression in people with breast or pancreatic cancer. Still another nanoparticle is in the second stage of clinical trials in the U.S. “With science like this, the initial stages take time, but I believe the field is starting to show promise,” Kataoka says. “The development speed will be much faster in the coming five years.”
DRUGS IN DISGUISE
Employing nanotechnology for chemotherapy drugs is not a brand-new idea. Medications such as Abraxane for metastatic breast cancer and Eligard for advanced prostate cancer, which are already on the market, are nanodrugs. But these pharmaceuticals attack only certain tumors, so more therapies are needed. Subsequent advances in engineering have allowed scientists to tweak the structure of nanocarriers so they work against a wider array of cancers with even greater precision. The nanotherapies now being tested—administered via an intravenous injection—seem to be more effective at eliminating tumors.
Most of these newer nanomedicines encase a drug-containing core in a soft sheath dotted with polyethylene glycol, a synthetic material that acts as a cloaking agent. That cloak is a covering of water molecules, which are attracted by the sheath material and thus surround it with a common body liquid. Water helps to block electrical charges from the particle that would otherwise alert the immune system to the presence of a foreign substance.
The liquid buffer also covers the nanoparticle’s edges, making it too smooth to provide purchase for any passing sentries from the immune system, such as antibodies. The size of the nanoparticle—somewhat larger than a traditional chemotherapy drug—also helps to ensure that it is not broken down too quickly by the body’s enzymes. That resistance to degradation gives the drug more time to reach a tumor and do its job. For example, the first approved nanotherapy for cancer, called Doxil, has a half-life in the bloodstream that allows it to survive much longer than its conventional chemotherapy cousin, doxorubicin. (Both drugs are used to treat ovarian cancer.) With its design and protective coating, the nanoscale version is better poised to get to tumors without being destroyed by the body. The soft, flexible texture of the newest nanoshell-type drugs also allows them to skip through one of their final obstacles: the dense, irregular ecosystem of the malig- nant tissue that could snag something more rigid.
The final weapon of the new nanoparticles lies within their inner depths. The drug-containing core can be broken down by acid, so it will readily disintegrate and shed its drug cargo only after it leaves the neutral environment of the blood and arrives at its tumor destination, which has much higher acid levels.
To better steer the nanocarriers toward cancers and away from healthy cells, other scientists are trying to dot their exteriors with selected antibody molecules that are attracted to proteins that are particularly abundant on cancer cells. Proteins such as EGFR are one such example, and University of California, Los Angeles, bioengineer Dean Ho has done preliminary experiments, published in Advanced Materials in 2013, showing that nanoparticles can be layered with antibodies that link to those proteins.
Nanoparticles can also be built to serve as actual medicines, not just the delivery vehicles. Scientists at Northwestern University created nanoparticles made from bits of gold and laced with genetic material—RNA—selected for its ability to silence cancer-causing genes. Because of the particles’ small size and other yet to be determined factors, gold nanoparticles studded with RNA can penetrate one of the hardest places to reach with a drug: the brain. In October 2013 researchers reported that, in animals, the nanoparticles can cross the blood-brain barrier—a tight mesh of small blood vessels—to help combat brain tumors. The approach caused overall tumor size to shrink in rodents, but ultimately the creatures still died from the cancer, says researcher Alexander Stegh of Northwestern. Exactly how this technique managed to clear the blood-brain barrier is still being explored, he notes. It is possible that the particles’ structure binds to receptor molecules on the surfaces of blood vessel cells, and the receptors help to pull them in.
Still other types of nanoparticles made from nucleic acids are being studied as probes to detect cancer cells that circulate through human blood. Chad A. Mirkin, a Northwestern chemist leading the project, says the research may lead to nanoparticles that carry both diagnostic chemicals and medicine—a formidable package that could eliminate hard-to-find cancerous cells before they spread to new places in the body. Devising that kind of tiny powerhouse would be no small feat.
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