Vascular CT contrast agent development

项目总结/摘要 我们的长期目标是通过计算机断层扫描（CT）彻底改变血管成像的有效性， 数百万美国人。对比增强CT是对多种形式的血管病变进行成像的首选方式。 由于使用方便和广泛的可用性。不幸的是，目前可用的CT造影剂是 严重受限于较差的血管增强，特别是在大到肥胖的患者中， 在对该患者人群成像所需的高kVp设置下，信号硬化和丢失。而且这些 所谓的“血管外细胞外”小分子试剂在血管内和 间质液，并因此提供关键静脉结构的“洗出”外观。考虑到 肥胖是心血管疾病的一个主要危险因素， 对于这种服务不足的人群，迫切需要具有改进的成像能力的造影剂。患者 对碘过敏的患者没有替代的CT造影剂选择。此外，碘造影剂是差的， 与血管钙化和含金属植入物（如支架）不同， 双能CT 我们建议开发一种安全的血池钽纳米颗粒造影剂（TaCZ），以解决这些问题。 未满足的临床需求。我们先前的工作表明，四种动物对TaCZ具有极好的耐受性， 高达6倍预期临床剂量和重复给药。TaCZ在体内和体外均显示出良好的上级X射线信号， 即使是在模拟的大体型中。TaCZ显示出具有血池分布的独特性质， 然而，令人惊讶的是，与临床碘化造影剂相当的快速肾排泄和最小的生物保留 剂.利用先进的CT成像金属伪影减少算法，TaCZ与碘化剂不同， 它保留了出色的信号，这使得它成为手术后或创伤患者成像的理想选择。持续时间 强烈的血管增强超过5分钟，不像碘化剂的5到10秒， 最大限度地降低血管成像时的错误和误时风险。TaCZ可以同时用于 碘造影剂作为不同的“颜色”在双能CT成像，以产生前所未有的 信息丰富的共配准彩色对比CT图像，扫描仪单次扫描5秒。在我们 项目建议书，我们将确定工艺和规格，为规模扩大TaCZ合成紧凑的大小 分布临床前毒性数据将扩展至包括最大可行的腹膜内和GLP 最大静脉内重复剂量测试，以使FDA-IND。然后首次在人体临床1期测试将 评估在正常和肥胖个体中的安全性和有效性。在这个项目结束时，我们将有 FDA-NDA批准所需的适用于临床2期和3期人体试验的验证数据， 这种变革性CT造影剂的商业用途。

Project Summary / Abstract Our long-term goal is to revolutionize the effectiveness of vascular imaging by computed tomography (CT) for millions of Americans. Contrast-enhanced CT is the modality of choice for imaging many forms of vascular disease due to ease of use and wide availability. Unfortunately, currently available CT contrast agents are severely limited by poor vascular enhancement, particularly in large-to-obese patients because of beam hardening and loss of signal at the high kVp settings needed to image this patient population. Moreover, these so-called “extravascular extracellular” small-molecule agents equilibrate rapidly between the intravascular and interstitial fluid, and hence provide a “washed out” appearance of critical venous structures. Considering that obesity is a major risk factor for cardiovascular disease and is increasing in prevalence, a transformative contrast agent with improved imaging capabilities is urgently needed for this poorly served population. Patients with an allergy to iodine are without alternative CT contrast options. Furthermore, iodine contrast is poorly distinguished from vascular calcifications and metal-containing implants such as stents, despite the advent of dual energy CT. We propose to develop a safe blood pool tantalum nanoparticle contrast agent (TaCZ) to address these urgent unmet clinical needs. Our prior work showed excellent tolerance to TaCZ in four animal species, even up to 6X intended clinical dose and with repeat dosing. TaCZ shows superior X-ray signal in vivo and in vitro, even in simulated large body habitus. TaCZ shows the unique property of having both a blood pool distribution yet, surprisingly, rapid renal excretion and minimal biological retention on par with clinical iodinated contrast agents. With advanced metal artifact reduction algorithms for CT imaging, TaCZ is unlike iodinated agents in that it retains excellent signal, which makes it ideal for imaging post-surgical or trauma patients. The duration of intense vascular enhancement is over 5 minutes, unlike for iodinated agents’ 5 to 10 seconds, which minimizes risk for error and mis-timing at vascular imaging. Profoundly, TaCZ may be used simultaneously with iodine contrast agents as different “colors” at dual energy CT imaging to generate unprecedented information-rich co-registered color contrast CT images with a single 5 second pass of the scanner. In our project proposal, we will define processes and specifications for scaled-up TaCZ synthesis for tight size distribution. Preclinical toxicity data will be extended to include maximum feasible intraperitoneal and GLP maximum intravenous repeat dose testing to enable FDA-IND. Then first-in-human Clinical Phase 1 testing will assess safety and efficacy in normal and obese individuals. At the conclusion of this project, we will have validated data suitable for the Clinical Phase 2 and 3 human trials required for FDA-NDA approval and commercial use of this transformative CT contrast agent.