Nanoshells Provide Golden "Touch" in Killing Breast Tumors
Gold nanoparticles have shown promise as miniature thermal scalpels that when irradiated with near-infrared light are capable of cooking tumors to death. Now, a team of investigators from The Methodist Hospital, Baylor College of Medicine, and The University of Texas M. D. Anderson Cancer Center have found that gold nanoshells can be used to deliver just a little heat to breast tumor cells already treated with radiation, boosting the killing power of both therapies. Indeed, as the investigators report in the journal Science Translational Medicine, the combination therapy not only shrank the tumors but dramatically decreased the population of cancer stem cells. This study was led by Jeffrey Rosen and Jenny C. Chang.
According to Baylor College of Medicine graduate student Rachel Atkinson, this was a serendipitous discovery. "I stumbled on this when I was a first-year graduate student. I was working with radiation and cancer stem cells, which are resistant to chemotherapy and radiation therapy. I had treated my cells with radiation and left them over the weekend. When I returned on Monday, I was disappointed because my cancer stem cells were dead and the normal cells were fine." She opened the incubator and her glasses fogged, giving her a clue that the temperature had gone up over the weekend. That was the clue that heat plus radiation appeared to be effective against the stubborn stem cells.
Ms. Atkinson repeated her experiment with different kinds of tumor cells and was about to publish her data when she learned of a group at M.D. Anderson that used nanoshells to deliver hyperthermia and to sensitize tumors to radiation therapy. These original studies had demonstrated hyperthermia delivered through nanoshells increases perfusion of tumors with oxygen and also focally disrupts the blood supply to tumors, both of which enhance the effectiveness of radiation. The Baylor and M.D. Anderson groups decided to collaborate to determine what effect heat delivered by the nanoshells would have in highly resistant tumors in mice. For their study, Ms. Atkinson chose two aggressive breast tumors that represent one of the worst breast cancer types - triple negative breast cancer, which lacks crucial receptors that can make it targetable with specific drugs. She also worked with mice that had human tumors of the same type.
When she treated the tumors with radiation alone, the tumors would shrink, but a large percentage of the cells left behind were cancer stem cells, which could regrow the tumor. Adding just a little heat - from 37 degree C (98.6 degrees F) to 42 degrees C (107.6 degrees F) - via the nanoshells reduced the population of stem cells dramatically. "The cancer stem cells were more sensitive to the combination treatment than the bulk of the tumor. This is the exact opposite response we see with radiation only," she said.
When Ms. Atkinson transplanted cells from the treated tumors into mice, she found that tumors were less aggressive and appeared more differentiated then tumors treated with radiation only. When she looked at the tumors that grew after transplantation, she found that the undifferentiated tumors had changed, becoming more differentiated with the formation of ducts and lumens typical of breast architecture.
"The advantage of the nanoshells is that you are not heating the whole mouse," said Dr. Rosen. Earlier studies of the effect of heat on cancer have used whole body heating, which can have serious side effects. In this case, the gold nanoshells, which are 100-nanometer silica spheres with gold shells, invade the tumor through the leaky blood vessels that provide it nourishment. The researchers used a near-infrared laser to heat the nanoshells for about 20 minutes.
"We were focusing on the cancer stem cells, not just the shrinking of the tumor. Decreasing the size of the tumor is not a good endpoint. You can shrink the tumor with drugs or radiation, but it does not kill the stem cells," said Rosen, who is a pioneer in the field. "What Rachel showed using mouse models and xenografts is leading to clinical trials in patients."
"These findings may have tremendous clinical implications. The use of gold nanoshells with heating and radiation could eliminate cancer stem cells as well as the bulk of the tumor, which may improve survival in women with breast cancer," said Chang.
Ms. Atkinson also found that with the addition of hyperthermia the cancer cells could not repair the damage done to their DNA and most of them died. The heat also prevented the cells from increasing levels of most of the heat shock proteins, she said. The only heat shock protein that increased may explain why some of the stem cells progressed to a more differentiated state.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Thermal Enhancement with Optically Activated Gold Nanoshells Sensitizes Breast Cancer Stem Cells to Radiation Therapy." An abstract of this paper is available at the journal's website.