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

项目总结/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效果。准确 肝肿瘤及其相关血管解剖的早期检测对于肿瘤分期、术前诊断和术后恢复至关重要。 计划和治疗监测。不幸的是，使用目前可用的造影剂，计算 断层扫描（CT）仅显示直径<1 cm的肝肿瘤的敏感性为60%，即使在现代研究中， PET/CT。可用的CT造影剂受到肝脏和血管增强差的严重限制，特别是 对于体型较大的患者，以及肾脏和过敏型禁忌症。肥胖与患癌症的风险较高有关 死亡率，但目前的CT剂在高kVp CT设置下表现特别差，需要成像这种 患者目前所有的CT试剂都使用碘，碘在高kVp下会损失高达50%的信号。这些所谓的 “血管外细胞外”试剂在血管内液和间质液之间迅速平衡，因此 提供关键结构的“洗出”外观。这些小分子造影剂不能 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，先前的实验性CT血池造影剂，可以量化血管生成还没有被发现。 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。我们 开发了一种可扩展的工艺来生产原型尺寸的氧化钽纳米颗粒造影剂（TaCZ 1 (3.1 nm），可提供出色的血池对比度、上级肝脏增强和快速肾脏清除 没有可观察到的肾脏病理。然而，降低TaCZ的粘度和渗透压摩尔浓度是期望的， 扩大其潜在的临床价值。我们的具体目标是：1）增加TaCZ粒度以降低渗透压摩尔浓度 2）证明TaCZ在临床转化准备中的安全性 作为造影剂;和3）显示该试剂的上级检测、表征和治疗监测， 肝肿瘤在项目结束时，我们将完成向临床翻译的重要一步， 变革性的钽基血池CT造影剂，定义了理想的纳米颗粒尺寸， 安全性、快速肾清除率和出色的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。

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.