Radiosensitization of thyroid cancer by cancer cell specific reduction of gold ions

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Abstract. Unlike differentiated thyroid cancer, which has good prognosis, anaplastic thyroid cancer (ATC) remains one of the most aggressive and fatal solid tumors, with a median overall survival (OS) as 4 months and disease-specific mortality approaching 100%. As a rare cancer, ATC comprises less than 2% of thyroid cancers, however, represents a disproportionately high ~ 50% percent of thyroid cancer deaths. External beam radiation therapy (RT) remains critical for unresectable disease and is an essential component of adjuvant therapy following surgery. Postoperative RT consolidates operative reduction of tumor volume and significantly improves patient survival following surgery. However, its fundamental utility is severely limited by the fact that some cancer cells are resistant to RT. Delivering higher doses of RT to the gross tumor volume to overcome radiation resistance has been limited by toxicity to the normal surrounding tissues. Sequestering gold nanoparticles (GNPs) within tumors to amplify radiation-induced secondary electron showers has gained traction in recent years as a means to escalate radiation dose in the vicinity of the nanoparticle thus confining higher dose to the tumor and sparing surrounding tissues. However, solid tumors, including ATC, are characterized by a complex microenvironment and dense stromal component that serves as a formidable physiological barrier to the delivery of drugs and nanoparticles. Here we propose a solution to overcome problems with specific radiosensitization of ATC cells in the context of a dense stromal environment by intratumoral delivery of an aqueous solution of gold ions (i.e., buffered chloroauric acid) instead of GNPs thus achieving the ultimate reduction in size of a therapeutic agent – an atomic scale. Our hypothesis is that small gold ions (i) will uniformly distribute throughout the tumor as their diffusion is not likely to be impeded by the stroma, and (ii) will be reduced to gold nanoclusters (GNC) after specific uptake by cancer cells that (iii) will result in cancer cell radiosensitization to RT. This hypothesis is based on our compelling preliminary data, demonstrating efficient synthesis of GNCs inside cancer cells, but not in normal cells, with evidence of efficient radiosensitization. In addition, a number of recent reports demonstrated intracellular synthesis of GNCs and GNPs from chloroauric acid by mammalian cells with a preferential nuclear localization of the nanoparticles further supporting our hypothesis. Interestingly, this phenomenon has not been previously considered for applications in radiotherapy. We see it as a highly innovative and exciting opportunity to greatly improve radiosensitization efficiency of cancer cells in situ. We envision clinical implementation of our approach as an added boost to significantly increase efficacy of RT in patients with ATC. We expect that changing the current paradigm from delivery of pre-made GNPs to in situ synthesis of GNPs by cancer cells will overcame delivery barriers in ATC tumors and will result in a highly significant sensitization of thyroid cancer cells to RT that can greatly improve treatment outcomes.