Gold nanoshell mediated hyperthermia enhances the efficacy of radiation therapy

Despite convincing evidence for hyperthermic radiosensitization, the invasive means of achieving and monitoring hyperthermia and the lack of good thermal dosimetry have hindered its use in routine clinical practice. A non-invasive method to generate and monitor hyperthermia would provide renewed enthusiasm for such treatments. Near-infrared absorbing gold nanoshells have been shown to accumulate preferentially in tumors via the enhanced permeability and retention effect and have been used for thermal ablation of tumors. We evaluated the use of these nanoshells to generate hyperthermia to evaluate the anti-tumor effects of combining gold nanoshell mediated hyperthermia with radiotherapy. Laser settings were optimized for hyperthermia in a mouse xenograft model to achieve a temperature rise of 40- 41°C in the tumor periphery and 37-38°C (ΔT=4-5°C) deeper within the tumors. The ΔT measurements were verified using both thermocouple and magnetic resonance thermal imaging (MRTI) temperature measurements. Tumor re-growth delay was estimated by measuring tumor size after treatment with radiation (10Gy single dose), hyperthermia (15 minutes at 40°C), and hyperthermia followed by radiation and control. Significant difference (p <0.05) in the tumor volume doubling time was observed between the radiation group (13 days) and combination treatment group (25 days). The immunofluorescence staining for the hypoxic, proliferating cells and the vasculature corroborated our hypothesis that the radiosensitization is in part mediated by increased initial perfusion and subsequent collapse of vasculature that leads to acute inflammatory response in the tumor. The increased vascular perfusion immediately after gold nanoshell mediated hyperthermia is confirmed by dynamic contrast enhanced magnetic resonance imaging.