Designing Magnetic Resonance Protein-based Contrast Agents with High Relaxivity

描述（由申请人提供）：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，可用于临床诊断，不受组织深度的限制。MRI技术应用的一个主要障碍是缺乏敏感性和特异性。该方法常规地使用造影剂来放大病理区域和正常组织之间的磁共振图像中的对比度。尽管在过去的二十年中，在开发具有改进的性质的造影剂方面已经取得了显著的进展，但是仍然非常需要开发在成像中具有甚至更高的对比能力并且靶向特定分子实体的造影剂。该项目的目标是开发一类新型的基于蛋白质的MRI造影剂，其对不同器官的对比能力显著提高，并适用于各种类型癌症和其他疾病的分子成像。本课题的目标一是研制高弛豫率的蛋白质造影剂。目的2是测试我们设计的药物在体内成像和确定在体内弛豫。此外，将使用小鼠测定LD 50和最大耐受剂量。此外，为了降低免疫原性，我们将通过PEG化修饰蛋白质造影剂。对修饰蛋白的免疫原性、血液循环时间、稳定性和药理学进行了研究。目的3是测试我们开发的造影剂用于培养癌细胞的疾病生物标志物的分子成像的可行性。我们提出的工作探索了一种新的机制，以克服一个主要的限制，低灵敏度和选择性的造影剂，促进诊断和监测治疗的各种疾病的MRI。

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.