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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要我们的长期目标是彻底改变数百万美国人的肿瘤成像准确性。肝脏肿瘤及其相关血管解剖学的早期检测对于肿瘤分期、术前治疗至关重要不幸的是，使用当前可用的造影剂，需要计算。即使在现代研究中，断层扫描 (CT) 对直径 <1 cm 的肝脏肿瘤的敏感性也仅为 60% PET/CT 可用的 CT 造影剂受到肝脏和血管增强效果差的严重限制，特别是对于较大的患者，肾脏和过敏型肥胖与较高的癌症风险相关。死亡率，但目前的 CT 试剂在成像此类图像所需的高 kVp CT 设置下表现特别差目前所有的 CT 试剂都使用碘，在高 kVp 下会损失高达 50% 的信号。 “血管外细胞外”制剂在血管内液和间质液之间快速平衡，因此这些小分子造影剂无法提供关键结构的“褪色”外观。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，之前可以量化血管生成的实验性 CT 血池造影剂尚未得到证实。转化为临床应用的部分原因是生物消除缓慢、合成过程复杂或毒性。开发了一种可扩展的工艺来生产原型尺寸的氧化钽纳米粒子造影剂 (TaCZ1) (3.1 nm) 可提供出色的血池对比度、卓越的肝脏增强效果和快速的肾脏清除率没有可观察到的肾脏病理学，但是，降低 TaCZ 的粘度和渗透压是可取的。扩大其潜在的临床价值我们的具体目标是 1) 增加 TaCZ 粒径以降低渗透压。和粘度并提高成像效益；2) 证明 TaCZ 的安全性，为临床转化做准备作为造影剂；以及 3) 展示该试剂卓越的检测、表征和治疗监测能力在项目结束时，我们将完成临床转化的重要一步。变革性钽基血池 CT 造影剂，定义了理想的纳米颗粒尺寸，以实现卓越的性能安全性、快速清除和出色的 CT 肝脏肿瘤肾脏成像，并评估了该药物的原发性和转移性肝肿瘤的检测、表征和治疗反应。