Thursday, December 06, 2007

Remotely Controlled Drugs

Nanoparticles can be activated by radio frequencies.

By Katherine Bourzac

Remote-controlled drugs: Nanoparticles implanted in model tumors in mice release a drug (dyed green) into surrounding tissues when the mouse is exposed to radio-frequency waves. Credit: Sangeeta Bhatia, MIT

The only way for doctors to verify that cancer drugs are reaching a patient's tumor is to scan patients after weeks of treatments to see if the tumor has shrunk. In the hopes of shortening this process, improving outcomes for cancer patients, and reducing the side effects of chemotherapy, MIT engineers are developing remote-controlled, multipurpose nanoparticles. These compounds act as both precise drug-delivery vehicles and contrast agents for magnetic resonance imaging (MRI).

Now the researchers have given the nanoparticles the ability to release their payload on command when heated up by low-frequency electromagnetic waves applied from outside the body.

The nanoparticles, made by Sangeeta Bhatia of MIT's Division of Health Sciences and Technology, are iron-oxide spheres bound to tumor-targeting peptides and strands of DNA. The DNA is in turn bound to drugs like cisplatin, a commonly used chemotherapy agent. The researchers heat up the iron-oxide cores using radio-frequency waves. When the nanoparticles heat up, the DNA "melts": the two strands that make up the double helix separate, freeing the drug from the nanoparticle.

The particles are tunable: the temperature at which a strand of DNA melts depends on its length. Doctors could administer a cocktail of nanoparticles tuned to release their payload at different temperatures, then sequentially activate multiple doses by applying different radio frequencies.

Other groups are working on using nanoparticles for targeted chemotherapy. But these techniques are either passive--that is, the release of the drug cannot be controlled but happens over time--or have not worked very well, says Erkki Ruoslahti, a professor at the Burnham Institute for Medical Research, who is working on the nanoparticles with Bhatia. One alternative approach is to make hollow metal particles with drugs inside, then melt them with lasers. But, says Ruoslahti, these systems are complicated: the lasers must be trained on the tumors. Radio-frequency waves can be applied to the entire body with no ill effects and still activate Bhatia and Ruoslahti's nanoparticles.

Bhatia and Ruoslahti have demonstrated their remote-controlled nanoparticles in mice implanted with model tumors made of gel. Radio frequencies applied from outside the mice triggered the release of model drugs that penetrated the surrounding tissue. Earlier this year, the pair demonstrated that the nanoparticles home to tumor blood vessels and amplify their own aggregation. "When you get one or a group of nanoparticles to target, they call in more particles," says Ruoslahti. The process mimics the clotting of blood platelets.

The nanoparticles could serve several different functions. "The patient wouldn't have to come in for imaging, then chemotherapy, then repeated scans," says Bhatia. MRI scans administered at the time of treatment would verify that the drug has indeed reached the tumor: the iron-oxide cores of the nanoparticles act as an MRI contrast agent.

The researchers are also developing the nanoparticles for RNA interference, a promising therapeutic method that has been held back by problems with delivery. In RNA interference, specially designed sequences of RNA dampen expression of particular genes. Companies such as Alnylam hope to harness the process to therapeutically shut down disease genes, but delivery remains "a critically important problem to solve," says Phillip Sharp, MIT Institute professor and a cofounder of the company. Sharp is collaborating with Bhatia to develop nanoparticles to deliver RNA. For these purposes, the RNA would replace the DNA tether, and "the tether itself would be the drug," says Bhatia.

"The paradigm is to integrate detection and therapy," she says.