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

描述(申请人提供)：限制MRI应用于肝脏微小病变和转移的早期检测和基于疾病生物标记物的分子成像的靶向治疗的患者选择的主要障碍是由于缺乏所需的能够增强正常肝脏组织和肿瘤之间的对比度的MRI对比剂，这些对比剂具有高弛豫度、肿瘤靶向性、高肿瘤内分布和无毒性。目前临床上批准的对比剂的低灵敏度与低弛豫度有关，这对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。为了满足这一关键需求，我们(亚特兰大的Jenny J.Yang博士的团队)开发了一种新型的基于蛋白质的MRI造影剂，与临床MRI造影剂相比，这种造影剂的R1和R2弛豫度均有显著改善，在小鼠模型中的体内剂量效率得到改善，能够进行T2/T1比值变化的体内成像，并且毒性和免疫原性都很低。STTRI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和肿瘤特异性的蛋白质造影剂(PROCAS)，获得原则证据，以实现对肝脏肿瘤和葡萄膜黑色素瘤转移的早期检测，并显著提高灵敏度和选择性。目的1是利用移植的小鼠模型，开发具有理想稳定性和灵敏度的肝脏特异性肿瘤成像造影剂。目的2利用移植性黑色素瘤和正交性黑色素瘤转移模型，研制高精度的肝肿瘤特异性分子成像造影剂。将与临床批准的MRI造影剂Eovist/Priost进行比较，并进行详细的组织学分析。在第二阶段研究中，我们将调查安全性、免疫原性以及它们在监测靶向治疗反应和应用于影像引导手术方面的有效性。这些拟议的研究将为肝转移瘤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.