A Spectral of Library Nanoparticle Contrast Agents for Spectral (Color) X-ray Imaging

该奖项由圣母大学材料研究部生物材料项目颁发，旨在开发用于光谱（彩色）x射线成像的纳米颗粒x射线造影剂光谱库。该奖项由化学、生物工程、环境和运输系统分部的微粒和多相过程项目共同资助。能量敏感x射线探测器的最新进展使得光谱计算机断层扫描（CT）通过分离不同材料的能量依赖衰减曲线而成为可能。这项技术的商业化有望给x射线成像带来一场新的革命。然而，生理液体和软组织的光谱差异足够小，需要造影剂来充分利用光谱CT。因此，为了充分发挥光谱CT的能力，需要基础材料研究来设计x射线造影剂的光谱库。在临床前研究中，对比剂最合适的组合是未知的，甚至是不可用的。纳米颗粒的核心成分将被定制，以包括包裹在硅壳中的高原子序数材料；这些将根据已知的x射线吸收光谱（K-， l -吸收边缘）诊断不同的核心元素（Au, Bi, Ce， Gd和Hf）来表征。纳米颗粒外壳将为选择具有胶体稳定性、细胞相容性和/或靶向性的分子配体的表面功能化提供一个公共平台。这种设计将导致一个通用的，但广泛适用的光谱库，可适应不同的需求，例如通过控制纳米颗粒大小和表面功能化来被动或靶向递送。本项目更广泛的影响包括：1)为研究实验室的本科生和高中生提供研究培训和指导；2)将本研究纳入靶向纳米颗粒作为成像和治疗药物的教学内容，3)为生物医学提供新的诊断工具。在上个世纪，x射线成像一直是非侵入性成像的主要手段，使医生能够诊断和治疗疾病和损伤。20世纪70年代，计算机断层扫描（CT）的出现彻底改变了放射照相技术，使三维成像成为可能。最近的发展使光谱（彩色）CT首次成为可能。这项技术将导致x射线成像的新革命，但缺乏合适的造影剂来充分利用光谱CT的能力。在临床前研究中，对比剂最合适的组合是未知的，甚至是不可用的。因此，设计一套x射线造影剂的光谱库需要基础材料的研究。光谱CT结合本项目开发的纳米粒子x射线造影剂光谱库，将在生物医学领域产生重大影响。这种变革性的技术将使科学家和医生能够区分不同的材料、组织和液体，这是以前x射线成像无法做到的。因此，影响可能是深远的，影响任何临床前和临床x射线成像的研究，诊断和治疗疾病和损伤。关于外展活动，该项目将与圣母大学纳米科学与技术中心合作，为本科生提供研究培训。此外，高中生将在这个研究项目中接受培训，以激发他们对STEM主题的兴趣。通过将该项目的研究方法和结果纳入生物材料高级本科生和低级研究生课程的靶向纳米颗粒成像和治疗剂讲座，将完成研究和教学的整合。

This award by the Biomaterials program in the Division of Materials Research to University of Notre Dame is to develop a spectral library of nanoparticle X-ray contrast agents for spectral (color) X-ray imaging. This award is cofunded by the Particulate and Multiphase Processes program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems. Recent advances in energy-sensitive X-ray detectors have made spectral computed tomography (CT) feasible by unmixing the energy-dependent attenuation profile of different materials. The commercialization of this technology is expected to bring a new revolution to X-ray imaging. However, spectral differences in physiological fluids and soft tissues are sufficiently small that contrast agents are needed to take full advantage of spectral CT. Therefore, fundamental materials research is needed to design a spectral library of X-ray contrast agents in order to fully capitalize on the capabilities of spectral CT. The most appropriate combinations of contrast agents for spectral CT are not known and unavailable even for preclinical research. The core composition of the nanoparticles will be tailored to include materials with high atomic numbers encased in silica shells; these will be characterized with respect to known x-ray absorption spectra (K-, L-absorption edges) diagnostic for distinct core elements (Au, Bi, Ce, Gd and Hf). The nanoparticle shell will provide a common platform for surface functionalization with molecular ligands chosen to impart colloidal stability, cytocompatibility, and/or targeting. This design will lead to a common, but widely applicable, spectral library that is adaptable to different needs, such as passive vs. targeted delivery via control of the nanoparticle size and surface functionalization. Broader impacts of this project include: 1) providing research training and mentoring to undergraduate and high school students in the researchers laboratory; 2) incorporation of this research into instructional content on targeted nanoparticles as imaging and therapeutic agents, and 3) providing a new diagnostic tools for biomedicine.For the last century, X-ray imaging has been the primary means of non-invasive imaging enabling physicians to diagnose and treat disease and injury. Radiography was revolutionized in the 1970s by the advent of computed tomography (CT) which enabled three-dimensional imaging. Recent developments have made spectral (color) CT possible for the first time. This technology will lead to a new revolution in X-ray imaging, but suitable contrast agents are lacking to fully capitalize on the capabilities of spectral CT. The most appropriate combinations of contrast agents for spectral CT are not known and unavailable even for preclinical research. Therefore, fundamental materials research is needed to design a set of spectral library as X-ray contrast agents. Spectral CT, combined with a spectral library of nanoparticle X-ray contrast agents developed in this project, will have a significant impact in biomedicine. This transformational technology will enable scientists and physicians to differentiate various materials, tissues, and fluids, and this was not previously possible by X-ray imaging. Thus, the impact could be far-reaching, affecting any preclinical and clinical X-ray imaging for the study, diagnosis, and treatment of disease and injury. With resepect to outreach activities, this project will be providing research training to undergraduate students in collaboration with Notre Dame Center for Nano Science and Technology. Additionally, high school students will be trained in this reseach project to stimulate their interest in STEM topics. Integration of research and teaching will be accomplished by incorporating the research methods and results of this project into a lecture on targeted nanoparticles as imaging and therapeutic agents for an upper-level undergraduate and lower-level graduate course on Biomaterials.