Gold Nanoparticle Contrast Agents: MicroCT of Colon Cancer

描述（由申请人提供）：本提案旨在开发基于无毒金纳米颗粒的体内微ct x射线成像的新型造影剂，该造影剂将提供比现有造影剂更多的有用特性，包括：a)更长的成像时间，b)更高的对比度，以及c)靶向，肿瘤特异性成像。从物理上来说，对于微型CT和临床CT来说，金是一种比碘更好的对比元素，因为对于微型CT来说，光束的能谱可以调整到高于其12-14 kev的l边缘（例如50 kVp），而对于临床CT来说，它可以调整到高于金的80.7 kev k边缘（例如，使用Cu过滤后的150 kVp），从而优化了两种应用的图像对比度与噪声比。第一阶段的工作已经成功地成像了20 μ m的血管，并在活体动物中获得了血管模型，这是以前从未实现过的。使用金纳米颗粒也可以在体内检测到原位结肠小肿瘤。药物动力学和毒性也被证明是可以接受的。金抗体偶联物在体外被发现对结肠肿瘤细胞具有特异性靶向性。在第二阶段，靶向分子成像将扩展到动物。将优化抗cea抗体-金纳米颗粒在小鼠模型中的微ct检测。此外，肿瘤中的血管分子标记物也将成为研究的目标。进一步的毒性测试将用于证明或改进无毒的金造影剂的生产。研发工作将产生可供其他研究人员使用的产品。这项工作的好处将是：a)使高分辨率的体内CT对比检测和研究结肠肿瘤及其血管系统成为可能；b)引入造影剂产品，然后其他研究人员可以使用微型CT进行血管和靶向成像；c)解决并克服剩余的障碍，使这些药物可用于人类使用。如果成功，这一努力将产生更好的血池剂和第一种靶向CT造影剂，这是其他方法难以实现的目标。

DESCRIPTION (provided by applicant): This proposal seeks to develop new contrast agents for in vivo microCT x-ray imaging based on non- toxic gold nanoparticles that would provide additional useful features over current agents including: a) longer imaging times, b) higher contrast, and c) targeted, tumor-specific imaging. Physically, gold is a better contrast element than iodine for both microCT and clinical CT because, for microCT the beam's energy spectrum can tailored to be above its 12-14-keV L-edge (e.g. 50 kVp), while for clinical CT it can be tuned to be above gold's 80.7-keV K-edge (e.g., 150 kVp with Cu filtration), thus optimizing the image contrast-to-noise ratio for both applications. Phase 1 work has succeeded in imaging 20 mu m blood vessels and obtaining vascular casts in live animals with this approach, never before achieved. Small, orthotopic colon tumors were also detected in vivo using gold nanoparticles. Phamacokinetics and toxicity were also shown to be acceptable. Gold-antibody conjugates were found to be specifically targeted to colon tumor cells in vitro. In Phase II, targeted molecular imaging will be extended to animals. Anti-CEA antibody-gold nanoparticles will be optimized to detect small human colon tumors in a mouse model by microCT. Additionally, vascular molecular markers in tumors will also be targeted. Further toxicity testing will be done and used to demonstrate or refine production of non-toxic gold contrast agents. R&D effort will result in products offered that other investigators can use. The benefits of this work will be: a) the enabling of high resolution in vivo CT contrasted detection and study of colon tumors and their vasculature, b) the introduction of contrast agent products that will then be available to other researchers using microCTs that will enable vascular and targeted imaging, c) to address and overcome the remaining obstacles to make these agents acceptable for human use. If successful, this effort will produce superior blood pool agents and the first targeted CT contrast agent, goals that have been difficult to achieve by other approaches.