Enable Early and Sensitive In Vivo Detection of Liver Metastasis by Protein-based

描述（申请人提供）：限制MRI应用于早期检测小肝病变和转移以及基于疾病生物标志物的分子成像选择患者进行靶向治疗的主要障碍是由于缺乏能够增强正常肝组织和肿瘤之间的对比度的具有高弛豫性、肿瘤靶向性、高肿瘤内分布且无毒性的所需MRI造影剂。与目前临床批准的造影剂的低弛豫率相关的低灵敏度对MRI进一步应用于监测转移治疗的效果（包括图像引导激光消融）造成了额外的限制。为了解决这一关键需求，我们（亚特兰大的Jenny J. Yang博士团队）开发了一类新型的基于蛋白质的MRI造影剂，与临床MRI造影剂相比，其表现出r1和r2弛豫率的显著改善，小鼠模型体内剂量效率的改善，能够在T2/T1比例变化的情况下进行体内成像，并且毒性和免疫原性低。STTR I期研究的目标是通过优化和表征我们设计的具有肝脏偏好性和肿瘤特异性的蛋白质造影剂（ProCA），获得原理性证据，以实现早期检测肝脏肿瘤和葡萄膜黑色素瘤转移，并显著提高灵敏度和选择性。目的1：利用小鼠肝移植模型，研制具有理想稳定性和灵敏度的肝特异性肿瘤造影剂。目的二是研制一种特异性高、准确性高的肝肿瘤分子造影剂。将与临床批准的MRI造影剂Eovist/Primost进行比较，并进行详细的组织学分析。在II期研究中，我们将研究安全性、免疫原性及其在监测靶向治疗反应和图像引导手术应用中的有效性。这些拟议的研究将为肝转移的临床应用提供必要的结果。

DESCRIPTION (provided by applicant): The major barriers limiting the application of MRI to detect small liver lesions and metastasis at the early stage and patient selection for targeted therapy based on molecular imaging of disease biomarkers, are due to the lack of desired MRI contrast agents capable of enhancing the contrast between normal liver tissues and tumors with high relaxivity, tumor targeting, high intra-tumoral distribution and no toxicity. The low sensitivty related to low relaxivity of the current clinically approved contrast agents has posted additional limitations to the further application of MRI to monitor the effect of metastasis treatment, including image-guided laser ablation. To address the critical need, We (Dr. Jenny J. Yang's team in Atlanta) have developed a novel class of protein-based MRI contrast agents which exhibit significant improvement of both r1 and r2 relaxivities compared to the clinical MRI contrast agents, an improvement in in vivo dose efficiency in mouse models, is capable of in vivo imaging with T2/T1 ratiometric changes, and low toxicity and immunogenicity. The goal of STTR Phase I research is to obtain proof-of- principle evidence to achieve early detection of liver tumor and metastasis of uveal melanoma with significantly improved sensitivity and selectivity by optimizing and characterizing our designed protein-based contrast agents (ProCAs) with liver preference and tumor specificity. Aim 1 is to develop liver-specific tumor imaging contrast agents with desired stability and sensitivity using a transplanted mouse model. Aim 2 is to develop liver tumor-specific molecular imaging contrast agent with high accuracy using transplanted and orthotropic melanoma metastasis models. Comparisons with clinically approved MRI contrast agent Eovist/Primost and detailed histology analysis will be performed. In Phase II studies, we will investigate safety, immunogenicity, and their effectiveness in monitoring responses to targeted therapies and application to image-guided surgery. These proposed studies will provide necessary results for transition to clinical application for liver metastasis.