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

抽象的。与预后良好的分化型甲状腺癌不同，间变性甲状腺癌(ATC) 仍然是最具侵袭性和致命性的实体肿瘤之一，中位总生存期(OS)为4个月和 疾病特异性死亡率接近100%。作为一种罕见的癌症，ATC占甲状腺癌的比例不到2%， 然而，它占甲状腺癌死亡人数的50%，这一比例高得不成比例。外束辐射 治疗(RT)对不能切除的疾病仍然至关重要，是辅助治疗的重要组成部分。 在手术后。术后放疗巩固了手术后肿瘤体积的缩小并显著改善 手术后病人的存活率。然而，它的基本用途受到严重限制，因为一些癌症 细胞对RT有抵抗力。向大体肿瘤体积提供更大剂量的放射治疗以克服辐射 耐药性受到对周围正常组织的毒性的限制。隔离金纳米颗粒 (GNP)在肿瘤内放大辐射诱导的二次电子簇射在最近获得了吸引力 年作为一种手段，以增加纳米粒子附近的辐射剂量，从而将更高的剂量限制在 肿瘤和周围组织的保留。然而，包括ATC在内的实体瘤的特征是复杂的 微环境和致密的间质成分是分娩的强大生理障碍 药物和纳米颗粒。在这里，我们提出了一种解决方案，以克服特定的放射增敏问题 金水溶液瘤内注射致密间质环境中的ATC细胞 离子(即缓冲的氯金酸)而不是GNPs，从而实现了治疗性药物的最终尺寸缩小 代理-原子天平。我们的假设是，小金离子(I)将均匀地分布在整个肿瘤中 因为它们的扩散不太可能受到基质的阻碍，以及(Ii)将被还原为金纳米团簇(GNC) 在被癌细胞特异性摄取后，(Iii)将导致癌细胞对RT的放射增敏。这一假设是 基于我们令人信服的初步数据，证明了在癌细胞内高效合成GNC，但不是 在正常细胞中，有有效放射增敏的证据。此外，最近的一些报告表明， 具有优先选择核的哺乳动物细胞内从氯金酸合成GNCs和GNPs 纳米颗粒的定位进一步支持了我们的假设。有趣的是，这种现象并没有 以前考虑在放射治疗中应用。我们认为这是一个非常创新和令人兴奋的机会 以大大提高癌细胞的原位放射增敏效率。我们设想临床实施我们的 作为一种额外的助推剂，可显著提高ATC患者的RT疗效。我们期待着 改变目前的范式，从交付预制的GNPs到由癌细胞原位合成GNPs将 克服了ATC肿瘤的传递障碍，将导致对甲状腺癌的高度敏感化 细胞转化为RT，可以极大地改善治疗结果。

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.