Thermal Enhancement with Optically Activated Gold Nanoshells Sensitizes Breast Cancer Stem Cells to Radiation Therapy

Local hyperthermia with gold nanoshells sensitizes cancer stem cells to radiation treatment in mouse and human breast cancer preclinical models. A Midas Touch for Breast Cancer Treatment One of the biggest hurdles to beating breast cancer is that a small population of stem cell–like cells (CSCs) within the tumor are stubbornly resistant to radiation therapy and chemotherapy. It is this CSC subpopulation that is responsible for relapse after successful treatment with radiation and drugs. Atkinson and colleagues now take a nanotech approach to solving this problem. Working in two different mouse models of breast cancer, they use gold nanoshells to turn up the heat on CSCs, making them more sensitive to radiation therapy. To sensitize breast tumor CSCs to radiation treatment, Atkinson and colleagues engineered gold nanoshells (nanoparticles comprising a silica core with an ultrathin gold layer) that accumulate preferentially in solid tumors and can be activated by near-infrared light (which is able to penetrate tissues). When activated by a laser, the nanoshells cause local heating of the tumors in which they have accumulated. The investigators first tested their gold nanoshells in mice bearing breast tumors that were particularly aggressive and radioresistant. Using surface markers and flow cytometry, the authors found that these breast tumors contained a cell population similar to the CSCs of human breast tumors. They injected their gold nanoshells intravenously into the tumor-bearing mice and then exposed the animals to both near-infrared laser light and 6 gray of ionizing radiation. This dual treatment not only shrank the tumors but also decreased the number of CSCs. Atkinson and colleagues then transplanted the treated tumors into syngeneic recipient mice and found that the tumors had become less aggressive and more differentiated in response to the dual laser radiation treatment. The researchers then went a step further, repeating these experiments with human breast tumor biopsy samples propagated in mice. Once again, they saw that the nanoshell-induced heating effect rendered the human breast tumors and their CSCs much more sensitive to ionizing radiation. But how does the combined treatment work? The investigators demonstrated that nanoshell-induced heating prevented breast tumor cells from repairing DNA double-strand breaks induced by ionizing radiation, resulting in an increase in their radiation sensitivity. Although the gold nanoshells still require further testing, hyperthermia treatments are already in clinical trials, and ionizing radiation is a staple of cancer therapy. This suggests that the dual hyperthermia-radiation cancer therapy of Atkinson et al. should be amenable to translation to a clinical setting. Breast cancer metastasis and disease recurrence are hypothesized to result from residual cancer stem cells, also referred to as tumor-initiating cells, which evade initial treatment. Using both syngeneic mouse and human xenograft models of triple-negative breast cancer, we have demonstrated that a subpopulation enriched in cancer stem cells was more resistant to treatment with 6 gray of ionizing radiation than the bulk of the tumor cells, and accordingly their relative proportion increased 48 to 72 hours after ionizing radiation treatment. In contrast, we achieved a larger reduction in tumor size without a concomitant increase in the percentage of cancer stem cells by treating with local hyperthermia for 20 minutes at 42°C after ionizing radiation using intravenously administered, optically activated gold nanoshells. Forty-eight hours after treatment, cells derived from the tumors treated with ionizing radiation plus hyperthermia exhibited both a marked decrease in tumorigenicity and a more differentiated phenotype than mock- and ionizing radiation–treated tumors. Thus, we have confirmed that these cancer stem cells are responsible for accelerated repopulation in vivo and demonstrated that hyperthermia sensitizes this cell population to radiation treatment. These findings suggest that local hyperthermia delivered by gold nanoshells plus radiation can eliminate radioresistant breast cancer stem cells.