Designing Magnetic Resonance Protein-based Contrast Agents with High Relaxivity

描述（由申请人提供）：生物标志物如表皮生长因子受体EGFR和HER 2/Neu以及胃泌素释放肽（GRP）受体（GRPR）在各种疾病如乳腺癌和前列腺癌中高度表达，并在疾病进展和生存中发挥重要作用。它们也是靶向治疗的主要药物靶点。迫切需要开发用于诊断和选择患者的非侵入性和准确的方法，并监测生物标志物水平/分布及其在靶向药物治疗后的变化。使用MRI进行癌症生物标志物的分子成像可能会提高我们对临床前和临床药物治疗期间疾病和药物活性的理解。然而，缺乏能够增强正常组织和肿瘤之间的对比度的具有高弛豫性、肿瘤靶向性、高瘤内分布和无毒性的所需MRI造影剂是MRI应用于评估用于诊断的特异性生物标志物和监测药物效果的主要障碍之一。本研究的目标是开发基于蛋白质的MRI造影剂，用于未来的临床应用，进一步提高弛豫性，靶向能力和降低毒性，以准确监测两种生物标志物（HER 2/Neu和EGFR）在不同类型癌症中的表达水平和分布，并监测肿瘤对使用靶向治疗的治疗反应，显著降低金属毒性。目的1是通过改变结构来进一步增加弛豫率。 内配位壳层中的排列和优化外层配位中的弛豫性质。目的2是开发靶向造影剂，以监测肿瘤进展和治疗过程中HER 2和EGFR的表达和分布。目的3是在临床前模型中研究生物稳定性和毒性的安全性特征。除了提高我们对弛豫理论的理解，我们提出的研究，以提高弛豫，靶向能力，以及良好的肿瘤组织分布的设计造影剂有可能克服的主要障碍，在临床应用中的分子成像通过MRI评估特定的疾病标志物。检测一组相关疾病生物标志物的时间和空间变化，例如共享相同信号传导通路的HER 2和EGFR，将允许早期疾病诊断、监测疾病进展和通过靶向治疗的协同治疗、帮助患者选择和开发用于临床应用的新型靶向治疗。

DESCRIPTION (provided by applicant): Biomarkers such as the epidermal growth factor receptors EGFR and HER2/Neu and gastrin-releasing peptide (GRP) receptors (GRPRs) are highly expressed in various diseases such as breast and prostate cancers and play important roles in disease progression and survival. They are also major drug targets for targeted therapy. There is an urgent need to develop non-invasive and accurate methods for diagnosis and selection of patients and to monitor biomarker levels/distribution and their changes upon treatment by targeted drugs. Molecular imaging of cancer biomarkers using MRI potentially improves our understanding of the disease and drug activity during preclinical and clinical drug treatment. However, lack of desired MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, tumor targeting, high intratumoral distribution and no toxicity is one of the major barriers for the application of MRI to assess specific biomarkers for diagnosis and monitor drug effect. The goals of this research are to develop protein-based MRI contrast agents for future clinical application with further improved relaxivity, targeting capability and reduced toxicity to enable accurate monitoring of the expression level and distribution of two biomarkers (HER2/Neu and EGFR) in different types of cancers, and to monitor tumor response to treatment using targeted therapeutics with significantly reduced metal toxicity. Aim 1 is to further increase relaxivity by varying structural arrangements in inner coordination shell and optimizing relaxation properties in outer sphere coordination. Aim 2 is to develop targeted contrast agents to monitor the expression and distribution of HER2 and EGFR during cancer progression and treatment. Aim 3 is to study the safety profiles for biostability and toxicity in preclinical models. In addition to improving our understanding of the relaxation theory, our proposed study to improve the relaxivity, targeting capability, and good tumor tissue distribution of the designed contrast agents has potential to overcome the major barriers in the clinical application of molecular imaging by MRI to assess specific disease markers. Detecting the temporal and spatial changes of a set of related disease biomarkers such as HER2 and EGFR sharing the same signaling pathway will allow for earlier disease diagnosis, monitoring disease progression and the synergistic treatment by targeted therapy, aiding in patient selection, and development of novel targeted therapies for clinical applications.