A. Mulgaonkar, S. Moeendarbari, G. Hassan, W. Mao, Y. Hao, X. Sun
University of Texas Southwestern Medical Center,
Keywords: gold nanoparticles, radiation, X-ray, AuNP, radiosensitization
Summary:Introduction: External-beam radiation therapy has shown increased benefit post breast conservation surgery for treatment of metastatic tumors in the loco-regional area. However, increased radiation dose to treat resistant micro-metastases may result in potential risk to healthy tissues and other side effects. Gold nanoparticles (AuNPs) have been reported as radiosensitizing agents. Efficiency in radio-sensitization and tumor selectivity of the AuNPs is dependent on their physicochemical characteristics (solid core versus nanoshells, nanoparticle size) along with their intra-tumor concentration. Our previous work with hollow AuNPs (HAuNPs, 50 nm hollow core and 30 nm thick polycrystalline shell) in MDA-MB-231 cells demonstrated a significant enhancement of radiation damage by HAuNPs to cells exposed to X-radiation. The purpose of this study is to assess the effect of HAuNPs on the response of MDA-MB-231 breast cancer tumor xenografts to X-radiation. Methods: The mouse xenograft model was established by subcutaneously injecting 3 × 106 MDA-MB-231 cells in each shoulder flank. The tumors were allowed to grow to ~7 mm diameter before treatment. The in vivo study was performed by intra-tumor injection of HAuNPs or saline to 5 – 6 sites of each tumor followed by radiation therapy in 4 treatment groups (n = 7): HAuNP + Radiation (group A), saline + Radiation (group B), HAuNPs only (group C), saline only (group D). Each tumor mass in the mice was irradiated with a 10 Gy single fraction dose using a small animal irradiator (13 mA X-ray beam of 225 kVp). Tumor sizes were measured by both, calipers (every other day) and magnetic resonance imaging (MRI; weekly), before treatment (day 0) to the end point when a mouse tumor reached ~15 mm or ~10% of mouse weight. For tissue distribution of HAuNPs, blood and organs were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The survival analysis was conducted by Kaplan-Meier curves with log-rank test. Results: Tumor growth rate was higher in groups C and D mice than in groups A and B as measured by calipers and further validated by MRI. Survival curve analysis demonstrated that a significant tumor growth inhibition was observed in group A as compared to the other treatments (p-value < 0.05). As anticipated, radiation therapy resulted in tumor growth inhibition and the inhibition was further enhanced by HAuNPs. Owing to the size of the HAuNPs, >90% of the particles were found to be retained in tumors throughout the treatment, as determined by ICP-MS. Conclusion: A synergistic effect was observed in the survival rate of mice treated with both HAuNPs and radiation therapy compared to radiation therapy alone. This work has demonstrated an efficient method to improve the radiosensitivity and thus overall survival rate in the treatment of breast cancer.