Communication helps target tumors

Proteins and nanoparticles that talk in order to more efficiently locate and treat tumors could reduce collateral damage to healthy tissues.

Jun 20, 2011
Jessica P. Johnson

Mouse tumor imaging using targeted particlesBY KUEBI VIA WIKIMEDIA COMMONS

A new technique that uses nanoparticles and engineered proteins to broadcast the location of cancer in the body can deliver up to a 40-fold greater concentration of chemotherapy drugs to tumors than untargeted cancer treatments. The new technique, published online yesterday (June 19) in Nature Materials, could inform the development of more efficient therapies that lower required doses and minimize damage to healthy tissues.

“It’s elegant work,” said Mansoor Amiji, co-director of the Nanomedicine Education and Research Consortium at Northeastern University, who was not involved in the research. The system described could eventually open doors to new therapeutic designs for a variety of cancers, he added. “This applies to many different types of systems. It has versatility.”

A big hurdle in improving cancer treatments is the precise targeting of tumors. Restricting radiation therapies to the site of a tumor helps reduce the negative side-effects of less focused treatments, but identifying the tumors' exact location isn't always possible, and such treatments can still damage surrounding tissues. Another approach is to target chemotherapy drugs to tumors using nanoparticles that are attracted to cancerous tissues, but because the liver naturally filters the particles out of the body, large quantities of the therapeutic agent had to be injected in order to see a significant accumulation of the drug at the tumor.

“One of the greatest challenges of direct delivery [of chemotherapy agents] is how to get enough dose to the target," said Amiji. "On average, 50-60 percent of nanoparticles usually end up in the liver."

By designing a system of nanoparticle and protein components that can communicate with one another, biomedical engineer Geoffrey von Maltzahn of Flagship Ventures, an investment firm that helps launch new therapeutics and medical technologies companies, and his colleagues devised a nano-based system that can help localize cancers, as well as more efficiently deliver therapeutic agents to tumors, reducing the potential for collateral damage to healthy tissues.

The system involves two sets of molecular components -- signaling modules, which locate the tumor and trigger the blood in its vessels to coagulate, and receiving modules, which respond to the coagulation and deliver therapeutic agents to the tumors.

The researchers tested the effects of  various combinations of signaling and receiving modules on mice with human breast cancer tumors. The signaling modules -- either rod-shaped gold nanoparticles that have previously been shown to gravitate towards cancer, or tissue factor proteins engineered to find tumors undergoing angiogenesis -- traveled through the blood stream and accumulated in the tumors. Once they reached their targets, the engineered proteins bound to specific receptors that directly activated the blood in the nearby vessels to clot. For the gold nanoparticles, the researchers applied near-infrared light to heat the particles and damage the tumor’s blood vessels, triggering coagulation.

The initiation of coagulation then set in motion the second part of the process -- the delivery of drugs or imaging agents by the receiver modules. One receiver the researchers tested, fluorescently-labeled iron oxide nanoparticles coated with peptides that bind to regions of coagulation, acted as an imaging agent to highlight the cancer's location when imaged with an infrared system. The other, liposomes that were also coated with coagulation-seeking peptides, carried the chemotherapy drug doxorubicin to the tumors, which they released upon binding to proteins involved in clotting.

Researchers found that a single treatment with gold nanoparticles and liposomes led to an accumulation of doxorubicin in the tumors that was 40 times more concentrated than was delivered by liposomes not targeted to coagulation, and inhibited tumor growth in mice for the duration of monitoring (24 days), whereas the growth of tumors treated with untargeted liposomes did not slow. Iron oxide receivers paired with either the gold nanorods or the engineered proteins also improved tumor targeting up to 10-fold over iron oxide nanoparticles that were not being directed to tumors by signaling modules. In short, the coordination of the signaling and receiving modules enabled the more efficient delivery of drugs and imaging agents to the cancerous tissues.

“This is the first development of a system of communication between nanoparticles,” said Maltzahn. “This is a step towards thinking of nanoparticles collectively. It is a proof of concept that we hope will lead to the development of therapeutics.”

But inducing coagulation may not be the safest way to target cancer, said Amiji, as blood clots that get swept away in the blood stream could potentially block small vessels. “As long as the clot remains in the tumor, it is okay,” he said. “But if the clots break off, you could risk embolism.”

In addition, because the system is not yet 100 percent accurate, coagulation may be triggered in healthy tissues, or therapeutic agents may be delivered to non-cancerous tissues undergoing normal clotting. "It’s not clear that [coagulation] is the right system to move forward with because the question of specificity is still unclear,” said Maltzahn. Different nanoparticles that utilize different signaling pathways could improve targeting of specific cancer types, he suggested.

G. von Maltzahn, et. al.  "Nanoparticles that communicate in vivo to amplify tumour targeting," Nature Materials, doi: 10.1038/nmat3049, 2011.