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

通过基于蛋白质的方法实现肝转移的早期、灵敏的体内检测

• 批准号: 8714923
• 负责人: Jenny J. Yang
• 金额: $ 22.5万
• 依托单位: INLIGHTA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714923
• 关键词: Ablation; Address; Affinity; Albumins; Animals; Antibodies; Binding; Binding Sites; Biological Markers; CXCR4 gene; Cell Line; Cessation of life; Clinical; Contrast Media; Death Rate; Detection; Development; Diagnosis; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; ERBB2 gene; Early Diagnosis; Effectiveness; Exhibits; Goals; Histology; Image; Image Guided Biopsy; Image-Guided Surgery; Ions; Lasers; Lesion; Liver; Liver neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Marketing; Melanoma Cell; Metals; Metastatic Melanoma; Metastatic Neoplasm to the Liver; Methodology; Modeling; Monitor; Mus; Neoplasm Metastasis; Patient Selection; Patients; Penetration; Pentetic Acid; Phase; Physiological; Post-Translational Protein Processing; Primary Neoplasm; Property; Prostatic Neoplasms; Proteins; Reagent; Reporting; Research; Resistance; Resolution; Risk; Safety; Sensitivity and Specificity; Small Business Technology Transfer Research; Staging; Toxic effect; Transplantation; Tumor Burden; Tumor Tissue; Uveal Melanoma; Xenograft procedure; Yang; base; clinical application; crosslink; design; imaging modality; immunogenicity; improved; in vivo; in vivo imaging; liver transplantation; melanoma; molecular imaging; mouse model; neoplastic cell; novel; phase 2 study; preference; public health relevance; ratiometric; response; treatment strategy; tumor; tumor specificity

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.

描述（由申请人提供）：限制MRI应用于早期检测小肝脏病变和转移以及基于疾病生物标志物分子成像进行靶向治疗的患者选择的主要障碍是由于缺乏所需的MRI造影剂能够增强正常肝组织与肿瘤的对比度，具有高弛豫性、肿瘤靶向性、瘤内分布高、无毒性等特点。目前临床批准的造影剂与低弛豫度相关的低灵敏度对进一步应用 MRI 监测转移治疗（包括图像引导激光消融）的效果造成了额外的限制。为了满足这一迫切需求，我们（亚特兰大 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，其 r1 和 r2 弛豫度均显着改善，这是一种改进在小鼠模型的体内剂量效率方面，能够进行 T2/T1 比率变化的体内成像，并且具有低毒性和免疫原性。 STTR I 期研究的目标是通过优化和表征我们设计的基于蛋白质的造影剂 (ProCA) 与肝脏的关系，获得原理证明证据，以显着提高敏感性和选择性，实现肝脏肿瘤和葡萄膜黑色素瘤转移的早期检测。偏好和肿瘤特异性。目标 1 是利用移植小鼠模型开发具有所需稳定性和灵敏度的肝脏特异性肿瘤成像造影剂。目标2是利用移植和正交各向异性黑色素瘤转移模型开发高精度的肝脏肿瘤特异性分子成像造影剂。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。在第二阶段研究中，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方面的有效性。这些拟议的研究将为向肝转移的临床应用过渡提供必要的结果。