Nanoparticle CT Contrast Agent for New Capabilities in Tumor Detection, Staging, and Therapy Planning and Response

纳米粒子 CT 造影剂在肿瘤检测、分期、治疗计划和响应方面具有新功能

• 批准号: 9920129
• 负责人: Brian Bales
• 金额: $ 82.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920129
• 关键词: Abdomen; Acute; Address; Adipose tissue; Allergic; American; Anatomy; Angiogenesis Inhibitors; Animals; Appearance; Attenuated; Blood; Blood Vessels; Caliber; California; Characteristics; Clinical; Clinical Trials; Collaborations; Complex; Computed Tomography Scanners; Contrast Media; Data; Detection; Diagnostic Neoplasm Staging; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Kinetics; Early Diagnosis; Effectiveness; Family suidae; Goals; Grant; High-Risk Cancer; Histologic; Human; Image; Impairment; Injections; Injury to Kidney; Intercellular Fluid; Iodine; Kidney; Liver; Liver neoplasms; Malignant Neoplasms; Medical Imaging; Metastatic Neoplasm to the Liver; Modality; Modeling; Modernization; Monitor; Neoplasm Metastasis; New Agents; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; Osmolalities; Outcome; Particle Size; Pathology; Patients; Peer Review; Phase; Physics; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Process; Rattus; Renal Agents; Renal clearance function; Research; Roentgen Rays; Safety; San Francisco; Signal Transduction; Staging; Structure; Tantalum; Testing; Thick; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Translating; United States National Institutes of Health; Universities; Validation; Variant; Viscosity; Woodchuck; Work; X-Ray Computed Tomography; angiogenesis; attenuation; base; cancer imaging; clinical translation; comparative; contrast enhanced; extracellular; improved; mortality; multidisciplinary; nanoparticle; preclinical imaging; preclinical safety; prototype; response; safety testing; small molecule; symposium; tantalum oxide; treatment response; tumor

PROJECT SUMMARY/ABSTRACT Our long-term goal is to revolutionize the effectiveness of oncologic imaging for millions of Americans. Accurate and early detection of liver tumors and their associated vascular anatomy is critical for tumor staging, pre-surgical planning, and treatment monitoring. Unfortunately, with currently available contrast agents, computed tomography (CT) only shows a sensitivity of 60% for liver tumors <1 cm in diameter, even in modern studies with PET/CT. Available CT contrast agents are severely limited by poor liver and vascular enhancement, particularly for larger patients, and renal and allergic-type contraindications. Obesity is associated with higher risk of cancer mortality, yet current CT agents perform particularly poorly at the high-kVp CT settings needed to image such patients. All current CT agents use iodine, which loses up to 50% of its signal at high kVp. These so-called “extravascular extracellular” agents equilibrate rapidly between the intravascular and interstitial fluid, and hence provide a “washed out” appearance of critical structures. These small-molecule contrast agents are unable to quantify angiogenesis, which is a universal characteristic of tumors that correlates with aggressiveness. Unfortunately, prior experimental CT blood-pool contrast agents that can quantify angiogenesis have not been translated to clinical use in part due to slow bioelimination, complex synthetic processes, or toxicity. We developed a scalable process to produce a tantalum oxide nanoparticle contrast agent (TaCZ1) of prototype size (3.1 nm) that provides outstanding blood pool contrast, superior liver enhancement, and rapid renal clearance with no observable kidney pathology. However, reduction in the viscosity and osmolality of TaCZ is desirable to broaden its potential clinical value. Our Specific Aims are to 1) Increase TaCZ particle size to reduce osmolality and viscosity and improve imaging benefits; 2) Demonstrate TaCZ safety in preparation for clinical translation as a contrast agent; and 3) Show the agent's superior detection, characterization, and treatment monitoring of liver tumors. At project conclusion, we will have completed a major step toward clinical translation of a transformative tantalum-based blood-pool CT contrast agent, defined the ideal nanoparticle size for excellent safety, rapid renal clearance, and outstanding CT liver tumor imaging, and assessed this agent for primary and metastatic liver tumor detection, characterization, and treatment response.

项目摘要/摘要 我们的长期目标是彻底改变数百万美国人的肿瘤学成像的有效性。准确的 肝肿瘤及其相关的血管解剖结构的早期检测对于肿瘤分期至关重要 计划和治疗监测。不幸的是，使用当前可用的对比代理，计算 层析成像（CT）仅显示直径<1 cm的肝肿瘤的灵敏度，即使在现代研究中 宠物/CT。可用的CT对比剂受到不良肝脏和血管增强的严重限制，尤其是 肥胖与癌症风险更高有关 死亡率，但是当前的CT代理在需要形象的高KVP CT设置下表现较差 患者。所有当前的CT代理都使用碘在高KVP处损失高达其信号的50％。这些所谓的 在血管内和间质液之间快速等效地等效地等效的“血管外细胞外”药物，因此 提供临界结构的“洗净”外观。这些小分子对比剂无法 量化血管生成，这是与侵袭性相关的肿瘤的普遍特征。 不幸的是，可以量化血管生成的先前的实验性CT血液池对比剂尚未 转化为临床用途，部分原因是生物启示缓慢，复杂的合成过程或毒性。我们 开发了一种可扩展的过程，以产生原型尺寸的氧化氧化纳米粒子对比剂（Tacz1） （3.1 nm）可提供出色的血池对比度，上肝增强和快速肾脏清除率 没有可观察到的肾脏病理学。但是，塔克兹的粘度和渗透率的降低是需要的 扩大其潜在的临床价值。我们的具体目的是1）增加Tacz粒径以减少渗透压 和粘度和改善成像益处； 2）在准备临床翻译的准备中展示塔克兹的安全 作为对比剂； 3）显示代理商的卓越检测，表征和治疗监测 肝肿瘤。在项目结论中，我们将完成朝着临床翻译的重大步骤 基于变形的触觉血液池CT对比剂，定义了理想的纳米颗粒尺寸 安全性，快速肾脏清除以及出色的CT肝肿瘤成像，并评估了该药物的原发性和 转移性肝肿瘤检测，表征和治疗反应。