Gold nanoparticles can absorb near infrared light, resulting in heating and ablation of tumors. Gold nanoparticles have also been used for enhancing the dose of X-rays in tumors during radiotherapy. The combination of hyperthermia and radiotherapy is synergistic, importantly allowing a reduction in X-ray dose with improved therapeutic results. Here we intratumorally infused small 15 nm gold nanoparticles engineered to be transformed from infrared-transparent to infrared-absorptive by the tumor, which were then heated by infrared followed by X-ray treatment. Synergy was studied using a very radioresistant subcutaneous squamous cell carcinoma (SCCVII) in mice. It was found that the dose required to control 50% of the tumors, normally 55 Gy, could be reduced to <15 Gy (a factor of >3.7). Gold nanoparticles therefore provide a method to combine hyperthermia and radiotherapy to drastically reduce the X-ray radiation needed, thus sparing normal tissue, reducing the side effects, and making radiotherapy more effective.

Gold nanoparticles (AuNPs) absorb light and can be used to heat and ablate tumors. The “tissue window” at ∼800 nm (near infrared, NIR) is optimal for best tissue penetration (∼2cm). Previously large, 50-150nm gold nanoshells and nanorods that absorb well in the NIR have been used. Here we show that small AuNPs, that may penetrate tumors better, barely absorb at 800nm. However, when conjugated to antitumor antibodies, they are taken up by tumor cells, which catalytically aggregate them by enzyme degradation and pH effects, thus shifting their absorption to the NIR region thereby amplifying their photonic absorption. The AuNPs are NIR transparent until they accumulate in tumor cells; this reduces background heating in blood and non-targeted tissues thereby increasing specificity in contrast to constructs that are always NIR absorbing. We show that treatment of subcutaneous EGFR overexpressing human squamous cell carcinoma (A431) tumor xenografts with 15nm AuNPs conjugated with anti-EGFR and NIR resulted in complete tumor ablation with virtually no normal tissue (skin) damage. Further, using radioresistant mouse squamous cell carcinoma SCCVII xenografts, we have combined AuNP-mediated infrared heating with x-ray therapy to take advantage of the well-known synergy of hyperthermia and radiotherapy. Lipoic Acid modified 15nm AuNPs were injected intratumorally by convection-enhanced delivery (CED) followed by NIR and X-ray therapy. It was found that the dose required for control of 50% the tumors, 55Gy, could be reduced to &lt;15Gy, a factor of 3.7 less. AuNPs therefore provide a method to use hyperthermia to reduce the x-radiation needed for tumor control, thereby sparing normal tissue, reducing side effects and making radiotherapy more effective. Citation Format: James F. Hainfeld, Michael J. O'Connor, Lynn Lin, Daniel N. Slatkin, F. Avraham Dilmanian, Henry M. Smilowitz. Gold nanoparticle-mediated infrared hyperthermia reduces the radiotherapy dose required for tumor therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 851. doi:10.1158/1538-7445.AM2014-851