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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的。与分化的甲状腺癌不同，甲状腺预后良好，甲状腺癌癌（ATC）仍然是最具侵略性和致命的实体瘤之一，中位总生存期（OS）为4个月，并且疾病特异性死亡率接近100％。作为一种罕见的癌症，ATC不到2％的甲状腺癌，但是，占甲状腺癌死亡的约50％的高度高。外束辐射治疗（RT）对于不可切除的疾病仍然至关重要，并且是调整疗法的重要组成部分手术后。术后RT巩固肿瘤体积的工作减少并显着改善手术后的患者生存。但是，由于某些癌症，其基本效用受到严重限制细胞对RT具有抗性。将更高剂量的RT输送到总肿瘤体积以克服辐射阻力受到对正常周围组织的毒性的限制。隔离金纳米颗粒（GNP）在肿瘤内扩增辐射诱导的二次电子淋浴，最近在最近的吸引多年作为在纳米颗粒附近升级辐射剂量的一种手段，因此将较高剂量限制在肿瘤和周围组织的保留。但是，包括ATC在内的实体瘤的特征是复合物微环境和密集的基质成分，可作为递送的强大物理障碍药物和纳米颗粒。在这里，我们提出了一种解决方案，以克服特定的放射敏化问题通过肿瘤内递送黄金的肿块，在致密的基质环境的背景下，ATC细胞离子（即缓冲氯龙酸）而不是GNP，从而实现了治疗尺寸的最终降低代理 - 原子量表。我们的假设是，小金离子（i）将在整个肿瘤中均匀分布由于它们的扩散不太可能受到基质的阻碍，并且（ii）将减少到金纳米簇（GNC）（GNC）。在癌细胞（III）的特定摄取后，将导致癌细胞放射敏化对RT。这个假设是基于我们引人注目的初步数据，证明了癌细胞内GNC的有效合成，但不是在正常细胞中，具有有效的放射敏化的证据。此外，许多最近的报告证明了哺乳动物细胞的细胞内合成GNC和GNP具有优先核的细胞。纳米颗粒的定位进一步支持我们的假设。有趣的是，这种现象还没有先前考虑过用于放射疗法的应用。我们认为这是一个高度创新和激动人心的机会极大地提高了原位癌细胞的放射敏化效率。我们设想我们的临床实施接近以增加ATC患者RT效率的增加。我们期望这一点将当前的范式从预制的GNP传递到癌细胞对GNP的原位合成将克服ATC肿瘤中的递送障碍，将导致甲状腺癌的高度显着灵敏度细胞到RT可以大大改善治疗结果。