For years now, scientists have been trying to make cancer treatments more effective and reduce their side effects, by packaging drug molecules inside other structures and delivering them only to cancer cells. It’s a much-needed effort, since current-day chemotherapy can nearly kill cancer patients, and even the strongest tolerable doses do not destroy some tumors.
But, so far, experimental treatments have helped only with the largest tumors, because the packages are too large to exit the bloodstream easily and infiltrate cells.
Now a researcher and physician at the University of Michigan has shown that manmade molecules called dendrimers can slip out of blood vessels and precisely deliver a drug to tumor cells, at least in mice. The dendrimers can also advertise their locations, allowing researchers to track their progress. The researcher, James Baker, plans to begin human trials in July.
Published last June in Cancer Research, Baker’s research helped his laboratory win $2.5 million in a new round of National Cancer Institute (NCI) funding announced last week. His hope is that the funding will push their research to the next level, and eventually give doctors the ability to monitor how individual cells in patients respond to drugs, then tune the treatments accordingly.
Baker’s funding is part of a five-year, $144 million NCI project designed to foster the use of nanotechnology to fight cancer. According to the president and chief technical officer of Dendritic NanoTechnologies, Donald Tomalia, who was one of the first to build dendrimers and is still exploring their uses for cancer detection and treatment, out of thousands of experiments published about dendrimers, Baker’s recent work has provided “one of the most exciting results.”
Resembling tumbleweeds, dendrimers are clusters of small molecules all linked to a central core. They have multiple attachment sites for other molecules. Baker linked multiple types of molecules to these attachment sites – over one hundred of the sites – including one that binds selectively to cancer cells, another that fluoresces (revealing the device’s location), and another commonly used as a chemotherapy agent.
In Baker’s experiments, the mice receiving traditional chemotherapy all died, from doses that turned out to be either too low or too high. When he used dendrimers, however, to deliver small doses of the drug directly to the cancer cells, some of the mice survived (the number varied according to the experiment). “A tumor that was not treatable with the free drug [was] treatable with the same drug targeted,” says Baker.
Because his dendrimers were also fluorescently labeled, Baker was able to see that the drug was indeed being delivered to the cancer cells.
So far, the technique has been shown to work only on head and neck squamous cancer in mice; but similar cancers, such as bladder and ovarian cancer, might also respond.
Baker’s nanotechnology approach overcomes one of the key obstacles to cancer treatment: getting drug molecules inside cancer cells. Because his dendrimers are small – about the size of a hemoglobin molecule (around 5 nanometers) – they can readily exit the bloodstream to get to tumors.
“With nanoparticles you’re working with materials that are small enough to get across mucosal barriers, across vascular pores, and actually find things like tumor cells and get into them and change them directly,” says Baker.
The dendrimers’ small size also means that once they’ve done their work and the cancer cells break down, they can be safely removed from the bloodstream by the kidneys.
Despite their current success, though, Baker’s method has drawbacks. For one, attaching many different molecules to one dendrimer is difficult, and, once completed, such a nanodevice will deliver only one drug to one kind of cancer cell.
To simplify manufacture, and add flexibility to the device, Baker is developing a way to make multiple dendrimers stick to each other, using complementary strands of DNA that act similar to the hooks and loops in Velcro. Each dendrimer would have just one function, such as drug delivery or targeting. Baker could then select dendrimers with the functions he needs and combine them in a solution.
At first, he will link just two dendrimers, but eventually group together several, making it possible to deliver multiple drugs along with fluorescing molecules.
A future application could involve tailoring drug combinations for specific people, based on observations of the uptake and effectiveness of each drug.
Some tumors have multiple types of cancer cells that require different drugs. The dendrimers could be used to detect which types of cells are present, and deliver the required drugs. They could also potentially track how individual cells respond to the drugs, allowing doctors to modify treatments.
Other groups are also working on multipurpose platforms for detecting and treating cancer. However, they have yet to show their devices can get out of the bloodstream and later out of the body. A group led by Mostafa El-Sayed of the Georgia Institute of Technology and his son Ivan El-Sayed of the University of California, San Francisco, has attached antibodies to gold nanoparticles, allowing the particles to selectively bind to certain cancer cells. Then light reflected from these particles reveals their location, and light absorbed by them causes the particles to heat up, destroying the cells they inhabit, but leaving healthy cells unharmed.
So far, the group has demonstrated its technology only in cell cultures. Although their particles are about eight times the size of Baker’s molecules, Ivan El-Sayed is hopeful that they can be delivered through the bloodstream. Eliminating them from the body is another matter, he admits – it may turn out that the particles can only be used in small doses to avoid a buildup of the gold.
Several other groups are also developing nanotech devices for cancer detection and drug delivery, including ones at MIT, Harvard, Virginia Commonwealth University, University of Missouri, University of Washington, and Rice University. “I think there’s going to be more and more involvement,” says Tomalia of Dendritic NanoTechnologies, because combining detection and treatment using nanotechnology “is a very appealing strategy.”
What’s more, delivering chemotherapy drugs using nanodevices is only the beginning, according to Baker. Researchers in his lab are also designing molecules that could act as artificial ion channels – tunnels through the cell membrane that could replace defective channels in diseases such as cystic fibrosis.
“The idea [with nanodevices] is to take advantage of the size of this material, get it into cells, and literally fix them,” says Baker.
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