The Programmable Pill

The patient leans back in his chair and closes his eyes, waiting to receive his first chemotherapy treatment for advanced colon cancer. His nurse locates the tiny catheter just beneath the skin of his chest and connects it to an IV tube. A clear fluid containing an anticancer drug travels down the tube, through the catheter and into the man’s blood vessels. The drug travels throughout his body in search of the fast-dividing cells characteristic of cancer-but only a relatively small portion of the drug will reach those cells. Instead, much of it will end up attacking hair follicles, immune system cells and tissues where noncancerous cells are dividing quickly. The treatment lasts an hour as the patient sits there, apprehensive not only about his disease but about side effects. Will he lose his hair? Will he feel nauseous? A few hours later, nausea sets in. By the next treatment, the hair loss he feared has begun.

Now fast-forward 10 years or so. Gone are the catheter and the shotgun approach. In their place is a remarkable little particle, invisible to the naked eye, that contains far more intelligence than the entire current system of drug delivery. Taken orally, the particle passes undisturbed through the stomach and small intestine and into the colon, where it homes in directly on the tumor cells. There, it releases a powerful anticancer drug that destroys just the cancerous cells-with no side effects.

Sound far-fetched? Well, it isn’t possible yet. But it could be quite soon, thanks to a new generation of “smart” delivery vehicles under development at a handful of universities and startup companies. These new methods offer the ability to precisely control the timing of a drug’s release. What’s more, they aim for laserlike targeting of just the right tissues and cells. And a little farther in the future lies the capacity to operate autonomously, gathering feedback from the body and adjusting treatment accordingly. The pioneers in this young field believe they will bring the first of these new weapons against disease into clinical trials as soon as five years from now, freeing patients from the pain and side effects of pills and injections, and also opening the door to whole new classes of treatments that aren’t possible with today’s delivery systems.

Gathering Speed

Smart drug delivery is still in its infancy-and at the same time it’s a discipline whose time has come. At the moment, most of the research is happening in academic labs, along with a few start-ups (mostly spun out of academe). But the promise of the technology is so great that it has caught the attention of large drug companies and other manufacturers. “They’re certainly poking around at conferences,” says Carl Grove, president of Columbus, OH, startup iMedd. “Even the Motorolas and the Intels, you see them nosing around too.” And though analysts have yet to offer their forecasts for the field, insiders often cite a 1998 report from the European Network of Excellence in Multi-functional Microsystems (an industry consortium funded by the European Union) predicting a worldwide market of $1 billion for microfabricated drug-delivery devices by 2002.

Much of this interest is driven by rapid progress in microfabrication. Researchers now have the ability to build devices with features small enough to interact with single cells, and even individual molecules. Getting the devices small enough is the key to their promise, says Mauro Ferrari, director of the Center for Biomedical Engineering at Ohio State University. “There are some major unsolved problems in medicine that can only be solved with micro- and nanotechnologies.”

When the delivery systems reach practicality, there’s a whole new suite of potential drugs waiting in the wings: proteins discovered as a result of the recent explosion of genomic information. But expanding the use of proteins as drugs demands much better means of delivery than are currently available, since most of these large biological molecules are either too potent to deliver through injection, or too fragile to withstand the enzymes and drastic changes in pH found in the stomach and intestines. With an entire new class of protein drugs in view, the enabling technologies in hand, and corporate interest growing, the next couple of years look like just the time for smart drug delivery to emerge as a field.

Perfect Timing

If this field is now poised for takeoff, it’s partly as the result of work going back a couple of decades. In the 1970s, MIT biomedical engineer Robert Langer worked out ways to build pills out of special polymers that dissolved at predictable rates to control drug dosages. Then, in 1993, Langer’s thinking on drug delivery leaped into the Information Age. “I was watching this TV show, and they were showing how computer chips are made, and I thought, boy, this would be a really neat way of making a drug-delivery system.” Langer buttonholed MIT material scientist Michael Cima and they set to work.

Their goal was to create an implantable microchip that could hold several years’ worth of medications, a miniature pharmacy that would dispense each dose automatically on schedule, freeing patients from complicated regimens. Five years later, Cima’s lab came up with a dime-sized silicon chip containing 34 drug reservoirs, each covered by a thin gold cap. Applying a small voltage to a given cap causes it to dissolve and release the reservoir’s contents.

The beauty of the device lies in its capacity to deliver drugs in a way that closely mimics how the body naturally produces chemicals-some in a steady stream, others in pulses. By carefully timing the voltage applied to each reservoir, the researchers could create different patterns of drug release. The chip could also hold many different kinds of drugs-a system that, conceptually, would work well for AIDS patients who must take 12 to 40 pills a day, at very specific intervals.

Last year, Cima and his colleagues successfully tested their system in animals. They implanted the chip in the back of a rabbit’s eye to simulate a treatment replacing the frequent eye injections required to combat vision loss from diabetes or macular degeneration. In the rabbit study, the researchers found that not only were they able to control the release of the drug, but the device itself didn’t cause any significant inflammation to the surrounding tissue.

Although this miniature pharmacy is promising, it still isn’t ready to run independently. The voltage on each reservoir must be controlled by an external power source connected to the chip via wires threaded through the animal’s tissue. Eventually, Cima hopes to make the entire system implantable by adding a tiny battery and a preprogrammed microprocessor. This will be the easiest part of the project, says Cima, who hopes to have a completely self-contained device ready for testing by the end of this year.

While the device is still under development, one of Langer and Cima’s former graduate students, John Santini, is gearing up to bring it to market. Encouraged by early lab successes, Santini founded Cambridge, MA-based MicroCHIPS in February 1999. The company has made its own improvements in the chip’s design, including squeezing up to 100 drug reservoirs onto some versions. Since each reservoir can hold only minute amounts of either powder or fluid, the company is focusing on using the chips for delivering potent drugs such as pain medications, anticancer agents, hormones and steroids. MicroCHIPS has also signed a deal with an undisclosed pharmaceutical company to develop chips carrying its proprietary drug; Santini hopes to have those chips ready for human trials in four to five years.

“People are finally starting to believe that microchip technology can be applied to drug delivery,” enthuses Santini. “Now we can take this technology and go in 50 different directions.” One possible direction: completely biodegradable polymer chips. Or a radio-controlled chip that would allow a doctor to reprogram the device remotely after implantation, should the patient need a new dosing schedule.

On Target

If the device that Cima has built specializes in complex scheduling, other groups are focusing on precise targeting. Take Ohio’s iMedd, one of the first companies in the field. IMedd was founded in Silicon Valley to commercialize the inventions of Ohio State’s Ferrari (then a professor at the University of California, Berkeley). When Ferrari went to Ohio in 1998, the company followed; but it continues to collaborate with former graduate students from Ferrari’s Berkeley lab.

One of them is Tejal Desai, now an assistant professor of bioengineering at the University of Illinois at Chicago. She and iMedd are building chiclet-shaped silicon particles so small (150 microns across and 50 microns thick) they’re invisible to the naked eye. On one side, the researchers etch from two to 20 drug-containing reservoirs, each sealed with a polymer plug. Like pills, the particles are swallowed, but unlike pills, they release drugs only at a predetermined time and location. “We want to make something that actually responds to the environment and interacts with the cells, instead of just going in and releasing a drug,” says Desai.

The targeting mechanism is a special coating deposited over the reservoir-bearing side. In initial experiments, Desai’s team is making particles aimed at delivering fragile drugs such as proteins directly to the bloodstream, so the researchers are coating the particles with a tomato protein called lectin that binds specifically to cells lining the intestine. The idea is that the particles could travel undisturbed through the harsh environment of the stomach, protected by the silicon casing. Once a particle reached the intestine, the lectin-coated side would bind to the lining. There, the system would ferry the drug quickly across the intestinal lining into the nearest blood vessel.

To get the job done, some of the reservoirs would hold chemicals to widen the spaces between the intestinal lining cells, and some would carry another chemical that blocks the enzymes that could degrade the drug. By modifying the polymer plugs covering the reservoirs, the researchers could make sure that the protective chemicals were released first. With these lines of defense in place, the drug could pass safely through the intestinal wall and into the bloodstream, and the empty particles could pass through the rest of the digestive tract.

Currently, Desai is testing the basic setup in rats. If that works out, she’ll begin adapting the particles for an array of targets. One idea is to replace the surface layer of lectin with an antibody that binds to tumor cells in the colon; that way, the particle could carry anticancer drugs directly to cancerous masses. Such a system could virtually eliminate side effects, revolutionizing treatment for the 130,000 or so patients who are diagnosed with colon and rectal cancer each year in the United States.

While Desai’s system offers great flexibility, in some cases intravenous delivery is still best. IMedd is therefore developing a polymer particle small enough for injection-just a few microns across-that will have the same targeting abilities as Desai’s prototype. “Now it gets even more complicated,” says Ferrari. “You need to make a delivery device that can perform multiple functions even at that size.” Derek Hansford, a biomedical engineer at Ohio State, is leading a project that aims to deliver just that. “The biggest challenge currently is in producing uniform particles with uniform material properties in large quantities,” says Hansford. Eventually, he plans to fill the particles with drugs and coat them with targeting agents in a system much like Desai’s.

Closing the Loop

A microscopic device stocked with drugs and a keen aim would be clever indeed, but the ultimate intelligent drug-delivery apparatus would also boast one more piece of equipment: a biosensor, which would enable it to respond to changes in the body’s chemistry and behavior. Coupled with a drug-delivery device, a biosensor could sense when concentrations of a drug were too high or too low, for example, and tell the device to respond accordingly-making the entire system not just smart but also autonomous.

Although almost all researchers in the field of smart drug delivery have an eye on biosensors, sometimes key advances come from outside the field-for example, from someone working directly on the sensors themselves. Take University of Michigan electrical engineer Kensall Wise, who is developing a tiny implantable neural probe, designed to measure electrical activity in the brains of patients with diseases like epilepsy or Parkinson’s disease. Wise quickly realized such a device could do double duty, delivering drugs to combat the very diseases it was monitoring, right where they were needed most.

An area where biosensors might have an even greater impact than they would in brain diseases is diabetes. Approximately 16 million people in the United States suffer from diabetes, making it the country’s seventh leading cause of death and one of its most costly chronic illnesses. Studies have shown that patients who diligently control their blood glucose levels can prevent or delay the secondary complications of diabetes-kidney and eye disease, for example-by up to 60 percent.

Finger-prick blood tests can tell patients what their sugar levels are at specific moments during the day, but they don’t say anything about the fluctuations between tests. Patients risk taking too much or too little insulin, both of which can cause serious and even life-threatening side effects. A glucose sensor implanted directly in the body and connected to an insulin-delivery device could solve those problems.

But nobody has come up with a glucose sensor that can survive an extended tour of duty, because the body’s response-scar formation-prevents delicate biosensors from making accurate readings. “The sensors are really the rate-limiting step in this whole thing,” says Texas A&M University engineer Michael Pishko. “Once we’ve got the sensor down, which is probably still five years away, fixing it to an insulin-delivery device will happen very quickly.”

Francis Moussy, a biomedical engineer at the University of Connecticut Health Center, believes he’s already found a solution. Moussy is developing a sensor smaller than a grain of rice that uses an enzymatic reaction to measure blood glucose levels. To evade scar tissue, Moussy plans to cover the sensor with tiny “microspheres,” beads made of a biodegradable polymer that he can fill with different chemicals. In the body, the microspheres would slowly degrade, releasing anti-inflammatory agents that block scar formation. Other microspheres would release a chemical to promote the growth of blood vessels near the sensor’s surface, giving the device greater access to glucose in the blood.

Confident that his system will work based on preliminary tests, Moussy is working on a design suitable for mass production. And since many smart drug-delivery devices are being designed to take advantage of manufacturing techniques already proven in the computer industry, there’s reason to think that scaling up production of the devices could go smoothly when the time comes. That time may be as little as a decade away. And it could mark the beginning of an era in medicine that is not only “smarter” but a whole lot more humane.