"cocktail" of cooperative nanoparticles seeks and destroys cancer tumors



US scientists have developed a "cocktail" of nanoparticles that work together in the bloodstream to seek, stick to and kill cancer tumors.

A paper describing the results of the project, which was funded by the National Cancer Institute of the National Institutes of Health, is to appear in a forthcoming print issue of the Proceedings of the National Academy of Sciences, PNAS, meanwhile an online version has been viewable since 28 December. The team behind the study comprises chemists from the University of California, San Diego (UCSD), bioengineers from the Massachusetts Institute of Technology (MIT), and cell biologists from the University of California, Santa Barbara (UCSB).

Senior author of the paper, Dr Michael Sailor, a professor of chemistry and biochemistry at UCSD, told the media that the study describes:

"The first example of the benefits of employing a cooperative nanosystem to fight cancer."

A nanosystem uses particles whose size is measured in nanometers. A nanometer is equal to one billionth of a meter, or one millionth of a millimeter, so a particle of a few nanometers is a thousand times smaller than the thickness of a single human hair.

In their study, Sailor and colleagues describe how they developed a system comprising two different types of nanomaterial: one designed to locate and stick to tumors in mice, and another to kill those tumors.

This is not the first time researchers have designed nanodevices to attach to diseased cells or deliver drugs targeted at particular diseased cells while leaving healthy ones alone, but until now, when trying to combine them, researchers found the devices didn't help each other.

Study co-author Dr Sangeeta Bhatia, a physician, bioengineer and a professor of Health Sciences and Technology at the Koch Institute for Integrative Cancer Research at MIT, and a Howard Hughes Medical Institute Investigator, described the problem of conflicting devices:

"For example, a nanoparticle that is engineered to circulate through a cancer patient's body for a long period of time is more likely to encounter a tumor."

But, as she explained:

"That nanoparticle may not be able to stick to tumor cells once it finds them. Likewise, a particle that is engineered to adhere tightly to tumors may not be able to circulate in the body long enough to encounter one in the first place."

The idea of a cocktail already works well with drugs: when a single drug doesn't work, a doctor will often prescribe a combination of several drugs, which in the case of cancer, serve to either tackle a single aspect of the disease, or to attack different functions simultaneously; either way, the combined effect is greater than either drug on its own.

Another problem in treating tumors with nanoparticles is that the immune system has cells called mononuclear phagocytes that do the same to them as what they are designed to do with cancer cells: they hunt them down, and take them out of circulation, which stops them reaching their target.

Thus one of the design goals of the new collaborative nanosystem was to develop two nanomaterials that would collaborate to overcome that problem, as well as others. This part of the work was led by Ji-Ho Park, a graduate student in Sailor's UCSD lab, and Geoffrey von Maltzahn, a graduate student in Bhatia's MIT lab.

One of the nanomaterials is made of gold nanorod "activators" that seep into a tumor through its leaky bloodvessels and collect there, until eventually there are enough to cover the whole tumor. These nanorods are little photothermal antennas that absorb otherwise harmless infrared laser irradiation and heat up the tumor.

The researchers injected gold nanorods into mice with epithelial tumors and let them circulate in their bloodstream for three days (so they permeated and covered the tumors) then heated them up with a weak laser beam to sensitize the tumors.

They found that "local tumor heating accelerates the recruitment of the second component", which they then injected into the mice.

They called this second nanomaterial the "responder": it comprised nanoparticles coated with a molecule that targeted the heat-treated tumor. They used two types of responder nanoparticles: either iron oxide "nanoworms" that light up in an MRI scan, or doxorubicin-loaded liposomes, hollow nanoparticles loaded with the anticancer drug doxorubicin.

The researchers showed that the drug-loaded responder was able to find a tumor, arrest its growth and then shrink it. Sailor said the nanoworms would be useful to help doctors locate and identify tumors, and measure their size and shape prior to surgery, whereas the hollow nanoparticles could be used to kill tumors without the need for surgery.

He described the collaborative system of activator and responder nanomaterials as being a bit like soldiers attacking an enemy base: one unit finds and the other eliminates the enemy:

"The gold nanorods are the Special Forces, who come in first to mark the target," said Sailor. "Then the Air Force flies in to deliver the laser-guided bomb. The devices are designed to minimize collateral damage to the rest of the body," he added.

The researchers said this study was significant because as Sailor explained:

"It is the first example of a combined, two-part nanosystem that can produce sustained reduction in tumor volume in live animals."

"Cooperative nanomaterial system to sensitize, target, and treat tumors."

Ji-Ho Park, Geoffrey von Maltzahn, Mary Jue Xu, Valentina Fogal, Venkata Ramana Kotamraju, Erkki Ruoslahti, Sangeeta N. Bhatia, and Michael J. Sailor.

PNAS published online before print December 28, 2009.

DOI:10.1073/pnas.0909565107

Source: MIT.

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Section Issues On Medicine: Disease