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Nanovalves for Drug Delivery

A new kind of nanoscopic valve that responds to pH changes may allow for the targeted release of drugs.
March 13, 2008

A new nanovalve that opens in response to pH changes could serve as the basis of a targeted drug delivery system. By filling a tiny, porous silica sphere with a drug and then plugging the pores with the valves, researchers can use pH changes to control the drug’s release.

Skewered donuts: A newly developed pH-sensitive nanovalve could help deliver drugs directly to diseased cells, bypassing healthy cells altogether. A tiny, porous silica sphere (dark blue) serves as a vessel for the drug (orange cubes). Each pore is stoppered by a nanovalve, which is composed of a donut-shaped molecule called cucurbituril (light blue) impaled on a molecular stalk (gray). In a chemical environment with neutral to acidic pH (top), the stalk and ring are tightly bound to one another. When the pH is basic (bottom), the ring falls off the stalk–unplugging the pore and releasing the drug. Slight differences in pH between diseased and healthy tissue may allow for precise targeting of the drug.

The pH of healthy and diseased tissues often differs, meaning the spheres could be designed to release the drug in diseased tissue only, says J. Fraser Stoddart, professor of chemistry at Northwestern University. Stoddart, along with UCLA chemistry professor Jeffrey Zink, led the development of the new nanovalve; their findings were announced in last week’s issue of the journal Angewandte Chemie.

Previous versions of the valve functioned only in organic solvents and were activated by elaborate oxidation reactions. By switching to a pH-activated mechanism, the researchers made the valve functional in water–a critical feature for any drug delivery system. “We’re now putting a lot of emphasis on systems that are biocompatible,” says Stoddart.

Other pH-sensitive nanovalves have been proposed, but “a lot of things we’ve worked on in the past are theoretical and can’t be made yet,” says Santiago Solares, an assistant professor of mechanical engineering at the University of Maryland who was not involved with the work. The new valve, on the other hand, has already been prototyped and tested for use in water.

The core of the system is a rigid silica nanosphere riddled with a honeycomb-like network of pores, which are filled with “guest molecules” that will be selectively released. In their test of the valves, the researchers used a dye called rhodamine as the guest molecule. If the system were used for drug delivery, the guest molecule would be the drug.

In addition to the guest molecules, a skewerlike molecular stalk is inserted into each pore. The stalk protrudes from the sphere’s surface, impaling a donut-shaped molecule called cucurbituril, which effectively plugs the pore and prevents the guest molecules from leaking out.

At just 400 nanometers in diameter, says Stoddart, the tiny spheres would easily be taken up by cells. Once inside, they would respond to the cells’ internal pH and either retain or release their contents.

At neutral to acidic pH, the cucurbituril is bound to the stalk by electrostatic forces, and the plug remains in place. But when the pH turns basic, these forces are disrupted, and the “donut” falls completely off its “skewer.” With the cucurbituril plug gone, the guest molecule–be it dye or drug–is free to leak out of the silica sphere’s pores.

The researchers are also experimenting with other, more specific mechanisms for triggering a drug’s release. For example, diseased cells might express a particular enzyme not present in their healthy counterparts. “If we can play to the presence of an enzyme–specifically in a diseased cell–to break a particular chemical bond, then we can introduce that chemical bond into the machinery,” says Stoddart.

Stoddart hopes that the new nanovalve system will eventually be employed for cancer treatment, where it could deliver drugs directly to tumor cells. Existing chemotherapy drugs come with nasty side effects, such as nausea and hair loss, precisely because they can’t distinguish different targets. “The drugs are as much bad news to healthy cells as they are to the diseased cells,” says Stoddart.

The nanovalve system might also be adapted to treat degenerative diseases where a particular cell type is affected, or for the controlled release of insulin to treat diabetes. Other, nonmedical applications–in food and cosmetics, or for environmental remediation–are also possible.

All these applications will require substantial modification and refinement of the nanovalve machinery. Ideally, the cucurbituril molecules would fall off their stems at a very specific pH, which could be tailored to specific applications. At the moment, that level of control remains elusive.

And while the valves have proven highly effective at controlling the release of dye in a test tube, their safety and efficacy in living systems have yet to be demonstrated. Tests on cells, animals, and eventually humans will be necessary before any potential medical applications can be realized.

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