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

癌细胞特异性还原金离子对甲状腺癌的放射增敏作用

• 批准号: 10569671
• 负责人: STEPHEN Y LAI
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569671
• 关键词: Acids; Adjuvant Therapy; Aftercare; BRAF gene; Biodistribution; Biological; Buffers; Cancer Cluster; Cancer Model; Cancerous; Carcinoma in Situ; Cell Nucleus; Cellular biology; Cessation of life; Clinical; Complex; Consolidation Therapy; Data; Development; Diagnosis; Diffuse; Diffusion; Disease; Dose; Drug Delivery Systems; Electrons; Environment; External Beam Radiation Therapy; Gold; Hafnium; In Situ; In Vitro; Ions; Kinetics; Literature; Malignant Neoplasms; Malignant neoplasm of thyroid; Mammalian Cell; Modeling; Mus; Natural regeneration; Normal Cell; Normal tissue morphology; Nuclear; Operative Surgical Procedures; Organ; Patients; Penetration; Physiological; Postoperative Period; Prognosis; Quality of life; Radiation; Radiation Dose Unit; Radiation therapy; Radiosensitization; Recording of previous events; Reporting; Rheumatoid Arthritis; Risk; Salts; Sodium Chloride; Solid Neoplasm; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Traction; Treatment outcome; Tumor Volume; Unresectable; anaplastic thyroid cancer; aqueous; cancer cell; cancer radiation therapy; chemoradiation; clinical implementation; clinical practice; clinical translation; cytotoxic; improved; in vivo; innovation; insight; irradiation; mortality; mouse model; nanoGold; nanocluster; nanoparticle; neoplastic cell; novel; radiation resistance; radioresistant; rare cancer; therapy outcome; therapy resistant; three dimensional cell culture; tumor; uptake

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.

抽象。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瘤之一，中位总生存期（OS）为4个月， 疾病特异性死亡率接近100%。作为一种罕见的癌症，ATC占甲状腺癌的不到2%， 然而，它代表了不成比例的高~ 50%的甲状腺癌死亡。外部射束辐射 治疗（RT）对于不可切除的疾病仍然至关重要，并且是辅助治疗的重要组成部分 手术后。术后RT巩固了肿瘤体积的手术缩小， 术后患者生存率。然而，它的基本效用受到一些癌症 将更高剂量的RT递送到总肿瘤体积以克服辐射 抗性受到对正常周围组织的毒性的限制。螯合金纳米粒子 （GNP）在肿瘤内放大辐射诱导的二次电子簇射的研究最近获得了关注。 作为一种手段，逐步增加纳米颗粒附近的辐射剂量，从而将更高的剂量限制在纳米颗粒上。 肿瘤和保留周围组织。然而，包括ATC在内的实体瘤的特征在于复杂的 微环境和致密的基质成分，作为一个强大的生理屏障的交付 药物和纳米颗粒的组合。在这里，我们提出了一个解决方案，以克服特定的放射增敏的问题， 通过瘤内递送金的水溶液在致密基质环境中的ATC细胞 离子（即，缓冲的氯金酸）代替GNP，从而实现治疗剂的尺寸的最终减小。 代理-原子尺度。我们的假设是小的金离子（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） 在癌细胞特异性摄取后，（iii）将导致癌细胞对RT的放射增敏。 基于我们令人信服的初步数据，证明了GNC在癌细胞内的有效合成， 在正常细胞中，具有有效的放射增敏性的证据。此外，最近的一些报告表明， 通过具有优先核的哺乳动物细胞从氯金酸细胞内合成GNC和GNP 纳米颗粒的定位进一步支持了我们的假设。有趣的是，这种现象并没有被 以前考虑用于放射治疗。我们认为这是一个高度创新和令人兴奋的机会 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 作为一种额外的增强方法，可显著提高ATC患者的RT疗效。我们预计 将当前的范式从递送预制GNP改变为通过癌细胞原位合成GNP， 克服了ATC肿瘤中的传递障碍，并将导致甲状腺癌的高度显著致敏 细胞进行RT，可以大大改善治疗效果。