SPECIAL REPORT
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One of the biggest problems with conventional drug delivery is that it is often ineffective at shuttling medicine to where it is needed in the body. For instance, the digestive system and the liver often thoroughly degrade orally delivered drugs before they can reach the bloodstream, making a variety of drugs such as those composed of proteins and peptides unsuitable for oral administration. Though injecting drugs into the body avoids the problem of first-pass metabolism, many drugs quickly decay after injection and the rate of drug absorption is typically difficult to control in that delivery route. Other drug-delivery methods face similar problems. “If you consider some of the common methods for delivery of protein and peptide drugs, you end up with a bioavailability that is often very low,” says John Santini, president and CEO of MicroCHIPS (Bedford, MA, USA; www.mchips.com [7]), a company that produces implantable microelectronic drug-delivery devices. “But protein pharmaceuticals are becoming an increasingly important class of drugs for treating chronic or life-threatening conditions such as diabetes, osteoporosis, and cancer.”
If drugs could be delivered more efficiently and to a specific region in the body instead of the bloodstream at large, they often could be administered at lower doses, alleviating problems with drug toxicity in the process. Not surprisingly, researchers are exploring a number of methods to accomplish that goal, which could result in a variety of novel technologies that could redefine drug delivery. “I see drug-delivery technology heading toward more localized, targeted, and controlled delivery in general,” explains Daniel Schmidt, a chemical engineering graduate student at Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) who is researching drug-delivery technologies for the school’s Hammond Research Group.
Looking to microelectronics and nanotechnology for inspiration, researchers’ quest to develop new delivery methods is partly driven by the growing popularity of biologics such as proteins, DNA, and RNA, which can’t be delivered orally. “Gene therapies could one day cure disorders for which currently only symptoms are treated,” Schmidt says. “Also, the recent discovery of small interfering RNA holds great promise for gene silencing as a method for treatment of disease.” But many biologics as well as large-molecule drugs have not found widespread use because they must be regularly injected into the bloodstream, making those promising new treatments, literally, a pain for the patient. As a result, many companies have also tried using pulmonary or nasal delivery for large-molecule drugs but have had limited success because the bioavailability can be low, which pushes up the cost of the drug since much of it is wasted, Santini explains. “And there can also be dangerous side effects from those paths of administration,” he adds, citing recent studies suggesting that inhaled insulin might increase pulmonary side effects. “In general, it’s preferable to administer the drug parenterally, delivering it to the same ‘body compartment’ being treated,” he explains.
Marrying Drug Delivery with Microtechnology
Santini’s company has developed a small implantable device that can deliver biologics or large-molecule drugs for up to six months in animal trials. Preliminary work on the project began in the early 1990s when Robert Langer, a prolific inventor and noted MIT professor, came up with the idea of using microchips to deliver drugs. “The ‘aha’ moment for Langer was when he got the idea of using microelectronics for something that had never been done before: using a chip to deliver a precise dose of a drug,” Santini says. Then a graduate student at MIT in Langer’s lab, Santini went on to found MicroCHIPS, a company that has been a pioneer for such technology.
The firm is currently developing a range of products that can deliver large-molecule drugs and biologics that can’t be delivered using conventional technologies. To store drugs on silicon wafers, the company adapted techniques commonly used in microfabrication to etch tiny reservoirs into a silicon chip’s surface. Because each reservoir is separate, the device can be loaded with a variety of drugs. “We offer very precise delivery of drugs from each one of our reservoirs and are applying this proprietary technology to a variety of new applications,” Santini explains.
Loaded with potent drugs, the reservoirs are sealed with an extremely thin platinum and titanium cap that is removed by initiating an electrothermal reaction. “It became very clear to us early on that we had to develop formulations that are much more potent and stable at body temperature than any pharma companies were offering,” Santini says. “We decided to work with proteins, peptides, and biologics that can’t be delivered via conventional means,” he explains.
Santini explains how the system’s ability to deliver multiple drugs can be put into effect: “The formulations from reservoir to reservoir can be different, so one of them is a quick release and others are slow release. Or multiple drugs could be loaded in different, separately sealed reservoirs to deliver a drug subcutaneously, or in the eye, or as part of a closed-loop monitoring and therapy system.”
The chips can be designed either to passively release drugs or to release them according to a doctor-prescribed regimen that is programmed into the device. When equipped with microchips, the system offers dosing precision that is unrivaled using other technologies, according to Santini. Drug release also can be triggered remotely using encrypted radio signals.
There is an array of potential drug-delivery applications for the technology. “At one end of the spectrum, you have conditions that require very precise doses of a drug to be delivered at a prescribed interval,” Santini explains. “The opposite of that are the conditions that require a continuous or constant release of a drug. In some cases, you need the device to be really small, which prohibits the use of electronics, so you have to deliver the drugs passively,” he says. “Our technology allows us to do both.”
The company is developing a system that can deliver an anabolic drug, parathyroid hormone, used to build new bone in osteoporosis patients. “To be effective, the drug has to be delivered in a pulsatile fashion rather than continuously,” Santini explains. “To create new bone without a long series of parathyroid hormone injections, you need exceptional control that can only be optimally achieved with electronics.”
Other applications of the company’s technology include inserting a drug-delivery device into the vitreous of the eye to treat macular degeneration. Two drugs have been recently introduced to treat the condition, both of which must be injected into the retina once a month. “Doctors make almost no money on this procedure, and, if you stop getting it, you go blind,” Santini notes. “Our system, which could be inserted into the vitreous, could deliver a drug for 2, 3, or maybe up to 6 months before you would have to go back to the doctor.”
The system also can be used in conjunction with other medical devices. For instance, a pacemaker equipped with a sensor and drug-delivery mechanism could release a life-saving drug in response to a heart attack. “There are times when a small amount of a drug delivered in vivo could make the difference of whether you get to the hospital alive or not,” Santini says.
Retooling Ink-Jet Technology for Drug Delivery
Another drug-delivery application that takes its inspiration from the microelectronics industry is an ink-jet system that can deliver accurate drug doses to the bloodstream. The result of research performed at Hewlett-Packard Co. (HP; Palo Alto, CA, USA; www.hp.com [10]), the drug-delivery platform uses ultrathin needles that can penetrate the skin without causing the pain often associated with hypodermic needles. The device is a skin patch containing microprocessors, a thermal unit, and up to 90,000 microneedles per square inch. Like the MicroCHIPS technology, the drug-delivery device is capable of storing and controlling the release of a variety of drugs using multiple, independent reservoirs. “The current prototype has between 300 and 400 wells that can hold about one microlitre per well,” explains John O’Dea, CEO of Crospon Ltd. (Galway, Ireland), which has licensed the technology from HP. “The total payload of the device would range between 300 to 500 µl and the prototype we are working on is about a square inch in size.”
The computer-controlled technology could be used with a variety of drugs and biopharmaceuticals. “Really, any drug can go in the wells,” O’Dea says. “But biologics are probably a more likely application area for us.” O’Dea cites pain management and post–cardiac surgery as other potential applications.
The microneedles on the device can be individually programmed to deliver medicine, varying the dose and time according to the patient’s needs. For instance, the system could be programmed to deliver drugs in response to specific changes in a patient’s blood pressure or heart rate. “Realistically, it will be three or four years before the device is ready to be marketed,” O’Dea predicts. “Our game plan is to have a working prototype in about a year.”
A Nanotech Prescription
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Capable of delivering a drug in response to the application of voltage, a thin film composed of nanoparticles of Prussian blue could be used to coat implantable medical devices.
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Though it has been slow to deliver on its promises, nanotechnology will, almost undoubtedly, revolutionize drug delivery. “Over the next 20 years or so, nanotechnology is going to transform healthcare,” says David Sarphie, a biotechnology professional and CEO of Bio Nano Consulting (London; www.bio-nano-consulting.com [11]), an organization launched in late 2007 to assist companies looking to commercialize medical applications of nanotechnology (see sidebar on page 35). “There are already drug-delivery technologies on the market that apply nanotechnology,” he adds. “And I see the number of nanotechnologies for drug delivery expanding rapidly in coming years—especially as big pharmaceutical companies look for new ways to delivery old drugs and extend patent life.”
Nanoscale drug-delivery systems are gaining attention because they can perform feats that were previously impossible: targeting tumors while leaving healthy cells unscathed, entering cell walls and attacking viruses within them, and shuttling drugs across the blood-brain barrier. In addition, nanoscale systems could lessen unwanted side effects by limiting a drug’s interaction with normal cells, and could travel incognito through the body, circumventing the body’s tendency to treat foreign substances as invaders.
Nanotechnology also could be used to actively control the release of drugs from thin films. Unlike conventional thin films used for drug delivery, which release drugs passively, a thin film developed at MIT containing nanoparticles of Prussian blue pigment can be made to dissolve in response to voltage, releasing a drug to a specific body region for treatment of diseases such as cancer, epilepsy, and diabetes. In addition, the film can be made to dissolve by using a telemetry system. “This is actually the same technology used to remotely open and close garage doors,” Schmidt says. “It involves a specific-frequency radio signal that triggers an electrical circuit to open or close.”
Typically measuring about 150 nanometers in thickness, the film is formed by binding layers of drug molecules with nanoparticles of negatively charged Prussian blue pigment, which is safe for use in humans, according to US FDA. The thin film dissolves when Prussian blue is exposed to voltage, thereby making it lose the negative charge that binds the film together. As a result, the film frees drug molecules trapped within its molecular matrix.
Because of the control made possible by forming them on the molecular level, the films can be directly applied onto irregular surfaces such as medical implants. Capable of being mass produced using a variety of techniques, the thin films could offer more design flexibility than microfabricated drug-delivery devices. “Our thin films could be part of an implantable microchip, or they could be coupled with existing biomedical devices such as stents, pacemakers, orthopaedic implants, tissue-engineering scaffolds, and so forth,” Schmidt says. “We expect a lead time of approximately five years until this technology is incorporated into medical devices.”
To improve cancer treatment, the Hammond Research Group at MIT is working on loading the films with a variety of chemotherapeutic drugs. “Currently, chemotherapy involves systemic delivery of highly toxic drugs that affect not just cancer cells but also tissues throughout the body,” Schmidt explains. The thin films have the potential of improving cancer treatment in a variety of ways. “First, implanting our films near a tumor site could allow localized delivery of chemotherapeutic agents, which would enable a lower effective dose to be used,” he says. “Second, it is known that cocktails of different chemotherapy drugs administered in sequence can have a particularly beneficial effect.” His group is now working on fabricating a multidrug array that would allow a physician to remotely trigger delivery of multiple different drugs at desired times. Schmidt also says that, because of the film’s ability to release anticancer drugs to a specific target, it could be used to stop tumor regrowth following excision, avoiding the need for additional surgeries.
Researchers at MIT are working on a number of other innovative drug-delivery applications, as well. Schmidt cites research on micellar nanocarriers with targeting ligands that can be injected intravenously for cancer therapy to localize in tumors and release chemotherapeutic agents. “For gene therapy, these materials can be designed to condense DNA, be transported into specifically targeted cells, and then release the genetic material for subsequent protein expression,” Schmidt explains. His research group is also working on hydrolytically degradable coatings that gradually erode under physiological conditions. “The drug loadings and release profiles can be precisely tuned by varying coating thickness and chemical composition,” he adds. Potential applications include the delivery of antibiotics, antiinflammatories, DNA, RNA, and proteins to treat an array of diseases. For instance, the films could be used to coat orthopaedic implants such as artificial hips or other joints to release painkillers, antibiotics, and growth factors in sequence. Another possibility would be coating intraocular lenses with antibiotics and antiinflammatories to minimize complications during cataract treatment.