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

项目摘要/摘要 我们的长期目标是为数百万美国人彻底改变肿瘤成像的有效性。准确 早期发现肝肿瘤及其相关的血管解剖对于手术前的肿瘤分期至关重要 计划和治疗监测。不幸的是，根据目前可用的造影剂，计算 体层摄影(CT)对直径<1厘米的肝脏肿瘤的敏感性仅为60%，即使在现代研究中也是如此。 PET/CT。现有的CT造影剂严重限制了肝脏和血管的强化，尤其是 适用于较大的患者，以及肾脏和过敏性类型的禁忌症。肥胖与患癌症的风险更高有关 死亡率，然而，目前的CT代理在成像所需的高KVP CT设置下表现得特别差 病人。所有目前的CT试剂都使用碘，在高KVP时，碘的信号损失高达50%。这些所谓的 “血管外细胞外”药剂在血管内和间质液体之间迅速平衡，因此 为关键结构提供一种“被冲刷”的外观。这些小分子造影剂无法 量化血管生成，这是肿瘤的普遍特征，与侵袭性相关。 不幸的是，以前可以量化血管生成的实验性CT血池造影剂还没有被 转化为临床使用的部分原因是生物消除缓慢、复杂的合成过程或毒性。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(TaCZ1) (3.1 nm)，提供卓越的血池对比度、卓越的肝脏增强和快速的肾脏清除 没有可观察到的肾脏病变。然而，降低TaCZ的粘度和渗透压是可取的 拓宽其潜在的临床应用价值。我们的具体目标是1)增加TaCZ的颗粒大小以降低渗透压 和粘度，并改善成像益处；2)在临床翻译准备中展示TaCZ的安全性 作为造影剂；以及3)显示该试剂优越的检测、表征和治疗监测 肝脏肿瘤。在项目结束时，我们将完成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、迅速的肾脏清除和出色的CT肝脏肿瘤成像，并评估了该试剂对原发和 转移性肝肿瘤的检测、特征和治疗反应。

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.