Manganese Dioxide Nanoparticles Increase Tumor Vulnerability To Radiation Therapy

Pretreating tumors with manganese dioxide nanoparticles may increase the efficacy of radiation therapy, according to a new study in mice. Tumors injected with the particles grew less after irradiation than untreated tumors did (ACS Nano 2014, DOI: 10.1021/nn405773r). The nanoparticles react with hydrogen peroxide in the tumors to correct chemical conditions that make tumors aggressive and thwart the effects of radiation.

Compared to healthy tissue, tumors have an abnormal chemical environment. Their leaky vessels do a poor job carrying in oxygen and shipping out metabolic waste, so tumors tend to be oxygen-poor and build up excess acid. These conditions can in turn make tumors aggressive, and can render them resistant to radiation and anticancer drugs.

The success of radiation therapy in particular depends on the tumor’s oxygen level. Patients with poorly oxygenated tumors don’t get as much benefit from radiation therapy because the treatment relies on oxygen molecules to produce reactive species that damage cancer-cell DNA. But these patients still get the side effects. Since about half of all cancer patients are treated with radiation, making this therapy more effective—and ideally, making it more effective at low doses that decrease side effects—would help a large number of patients, says Ralph S. DaCosta, a specialist in medical imaging and radiation oncology at the Princess Margaret Cancer Center, in Toronto.

Medical researchers have experimented with ways to deliver oxygen to tumors prior to radiation therapy, such as having patients breathe in highly concentrated oxygen or dosing them with artificial blood. But these approaches have not translated well to the clinic. And none of them address other chemical imbalances in the tumor environment, DaCosta says.

So he sought help from University of Toronto pharmaceutical chemist Xiao Yu (Shirley) Wu, who has been developing manganese dioxide nanoparticles for oxygen generation inside the body. Instead of carrying oxygen, these nanoparticles produce it by reacting with hydrogen peroxide and H+ ions, both of which are abundant in tumors. The reaction consumes the particles, releasing nontoxic manganese ions. By consuming H+ ions, the reaction also raises the pH.

To test the particles’ effects on tumors, the researchers injected them into breast cancer tumors in mice. Compared to untreated mice, animals injected with the nanoparticles had 45% higher levels of oxygenated hemoglobin in the blood vessels around their tumors. Imaging with pH-sensitive fluorescent dyes confirmed a return to normal pH levels, about 7.2, in treated tumors. And the treated tumors expressed lower levels of vascular endothelial growth factor and hypoxia-inducible factor 1, two proteins associated with aggressive tumors.

The team then irradiated the tumors. Tumors injected with the nanoparticles were 66% smaller five days after radiation therapy than irradiated tumors injected with saline. Further analysis showed that the cancer cell death rate was higher, 71%, in mice treated with both nanoparticles and radiation than in animals treated with radiation alone, about 40%.

The nanoparticles have a significant effect on tumor biology, says Robert J. Griffin, a radiation biologist at the University of Arkansas for Medical Sciences. Griffin says the group’s focus on making a therapy that corrects not only oxygen levels but also acidity is novel and promising.

However, he points out that injecting nanoparticles directly into tumors isn’t likely to be feasible for most patients, so the researchers need to find a way to administer the particles through the bloodstream. Wu says the group is formulating different versions of the nanoparticles, including one that can be given intravenously.