Designing Magnetic Resonance Protein-based Contrast Agents with High Relaxivity

描述(申请人提供)：生物标志物，如表皮生长因子受体EGFR和HER2/Neu以及胃泌素释放肽(GRP)受体(GRPR)在各种疾病中高度表达，如乳腺癌和前列腺癌，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。迫切需要开发非侵入性和准确的方法来诊断和选择患者，并监测生物标记物的水平/分布及其在靶向药物治疗后的变化。利用MRI对癌症生物标记物进行分子成像可能会提高我们对疾病的了解，以及在临床前和临床药物治疗期间的药物活性。然而，缺乏理想的磁共振造影剂能够增强正常组织和肿瘤之间的对比度，具有高弛豫度、肿瘤靶向性、高肿瘤内分布和无毒性，这是磁共振成像应用于评估特定生物标志物用于诊断和监测药物疗效的主要障碍之一。本研究的目标是开发基于蛋白质的磁共振造影剂，用于未来的临床应用，进一步提高松弛能力、靶向能力和降低毒性，从而能够准确监测两种生物标记物(HER2/Neu和EGFR)在不同类型癌症中的表达水平和分布，并监测肿瘤对靶向治疗的反应，同时显著降低金属毒性。目标1是通过改变结构来进一步增加松弛 内配位壳层排列和外球配位优化驰豫性质。目的2是开发靶向造影剂以监测HER2和EGFR在肿瘤进展和治疗过程中的表达和分布。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。除了提高我们对松弛理论的理解外，我们提出的提高松弛能力、靶向能力和良好的肿瘤组织分布的研究有可能克服MRI分子成像在临床应用中评估特定疾病标记物的主要障碍。检测一组具有相同信号通路的相关疾病生物标志物，如HER2和EGFR的时空变化，将有助于早期诊断疾病，监测疾病进展，通过靶向治疗实现协同治疗，帮助患者选择，并开发新的靶向治疗用于临床应用。

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.