Designing Magnetic Resonance Protein-based Contrast Agents with High Relaxivity

描述（申请人提供）：磁共振成像（MRI）是一种强大的非侵入性工具，具有高空间分辨率，不受组织深度的限制，可用于临床诊断。MRI技术应用的主要障碍是其缺乏敏感性和特异性。该方法常规使用造影剂来放大磁共振图像中病理区域和正常组织之间的对比度。虽然在过去的二十年里，造影剂的性能得到了显著的改善，但在成像和针对特定分子实体的造影剂方面，仍然需要开发更高对比度的造影剂。本项目的目标是开发一种新型的基于蛋白质的MRI造影剂，其对不同器官的造影剂能力显著提高，适用于各种类型的癌症和其他疾病的分子成像。本课题的目标1是开发具有高弛豫性的蛋白质造影剂。目的二是测试我们设计的药物在体内成像和确定体内松弛度。此外，LD50和最大耐受剂量将通过小鼠来确定。此外，为了降低免疫原性，我们将通过聚乙二醇修饰蛋白质造影剂。研究修饰蛋白的免疫原性、血循环时间、稳定性和药理学。目的3是测试将我们开发的造影剂应用于培养癌细胞的疾病生物标志物分子成像的可行性。我们提出的工作探索了一种新的机制，以克服对比剂低灵敏度和选择性的主要限制，促进MRI诊断和监测各种疾病的治疗。

DESCRIPTION (provided by applicant): Magnetic resonance imaging (MRI) is a powerful non-invasive tool with high spatial resolution for clinical diagnosis without the limitation of the depth of tissues. A major barrier to the application of MRI technique is its lack of sensitivity and specificity. The method routinely uses contrast agents to amplify the contrast in the magnetic resonance image between pathological regions and normal tissues. Although remarkable progress in the development of contrast agents with improved properties has been made in the last twenty years, there is still a great need for the development of contrast agents with even higher contrast capability in imaging and to target to specific molecular entities. The goal of this project is to develop a novel class of protein-based MRI contrast agents with significantly improved contrast capability for different organs and applicability in molecular imaging of various types of cancer and other diseases. In this proposal, Aim 1 is to develop the protein contrast agents with high relaxivity. Aim 2 is to test our designed agents in in vivo imaging and determine the in vivo relaxivity. In addition, LD50 and maximal tolerable doses will be determined using mice. Further, to reduce the immunogenicity, we will modify protein contrast agents by PEGylation. The immunogenesity, blood circular time, stability and pharmacology of the modified proteins will be investigated. Aim 3 is to test the feasibility of applying our developed contrast agents for molecular imaging of disease biomarkers with cultured cancer cells. Our proposed work explores a new mechanism to overcome a major limitation of low sensitivity and selectivity of contrast agents facilitating diagnosis and monitoring treatment of various diseases by MRI.