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.

摘要：与预后良好的分化型甲状腺癌不同，未分化甲状腺癌（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，作为一种罕见癌症，ATC 占甲状腺癌的比例不到 2%，然而，在甲状腺癌死亡中，外照射导致的死亡比例异常高，约为 50%。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术后放疗巩固了肿瘤体积的缩小并显着改善。然而，其基本用途受到某些癌症的严重限制。细胞对放疗有抵抗力向大体肿瘤体积提供更高剂量的放疗以克服辐射。抵抗力受到对正常周围组织的毒性的限制。（GNP）在肿瘤内放大辐射引起的二次电子簇射近年来受到关注作为增加纳米粒子附近辐射剂量的一种手段，从而将更高的剂量限制在然而，包括 ATC 在内的实体瘤的特点是复杂。微环境和致密基质成分作为分娩的强大生理屏障在这里，我们提出了一种解决方案来克服特定放射增敏的问题。通过瘤内输送金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，从而实现了治疗药物尺寸的最终减小剂 – 原子尺度。我们的假设是小金离子 (i) 将均匀分布在整个肿瘤中。因为它们的扩散不太可能受到基质的阻碍，并且 (ii) 将被还原为金纳米簇 (GNC) 被癌细胞特异性摄取后，(iii) 将导致癌细胞对 RT 产生放射敏感性。该假设是。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，但并非如此此外，最近的一些报告表明，在正常细胞中具有有效的放射增敏作用。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。以前考虑过在放射治疗中的应用，我们认为这是一个高度创新和令人兴奋的机会。我们设想将我们的技术应用于临床，以极大地提高癌细胞的原位放射增敏效率。我们预计，这种方法可以显着提高 ATC 患者的放疗疗效。将当前的范式从预制 GNP 的传递转变为癌细胞原位合成 GNP 将克服了 ATC 肿瘤中的递送障碍，并将导致对甲状腺癌的高度显着致敏细胞进行 RT 治疗，可以大大改善治疗结果。