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，可用于临床诊断，不受组织深度的限制。磁共振成像技术应用的一个主要障碍是缺乏敏感性和特异性。该方法通常使用造影剂来放大病变区域和正常组织之间的磁共振图像的对比度。虽然在过去的二十年中，性能改善的造影剂的发展取得了显著的进展，但仍然迫切需要开发具有更高成像对比度和靶向特定分子实体的造影剂。本项目的目标是开发一种新型的基于蛋白质的磁共振造影剂，显著提高对不同器官的对比能力，并适用于各种类型的癌症和其他疾病的分子成像。在这个方案中，目标1是开发高弛豫度的蛋白质造影剂。目标2是在活体成像中测试我们设计的试剂，并测定体内弛豫度。此外，将用小鼠测定LD50和最大耐受量。此外，为了降低免疫原性，我们将通过聚乙二醇化修饰蛋白质造影剂。将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研究。目的3是测试我们开发的造影剂用于培养的癌细胞对疾病生物标志物进行分子成像的可行性。我们的工作探索了一种新的机制，以克服造影剂灵敏度和选择性低的主要限制，便于通过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.