Non-invasive staging of Metastasis by Precision MRI

通过精密 MRI 对转移进行无创分期

• 批准号: 10552215
• 负责人: Jenny J. Yang
• 金额: $ 95.42万
• 依托单位: INLIGHTA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552215
• 关键词: Address; Affinity; Binding; Biodistribution; Biopsy; Blood; Caliber; Canis familiaris; Cells; Clinical; Collagen; Colorectal Cancer; Contrast Media; Data; Detection; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Excision; Exhibits; Extracellular Matrix Proteins; Extrahepatic; Fibroblasts; Formulation; Grant; Hepatic Stellate Cell; Heterogeneity; Histologic; Image; Investigational New Drug Application; Ionizing radiation; Ions; Kinetics; Lead; Lesion; Liver; Liver Fibrosis; Location; Lysine; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medical; Metals; Metastatic Neoplasm to the Liver; Methodology; Methods; Modeling; Modification; Molecular; Molecular Target; Mus; N-terminal; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Oxidases; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Patients; Permeability; Pharmaceutical Preparations; Phase; Process; Proteins; Quality of life; Radiologic Finding; Recurrence; Reporting; Resectable; Resolution; Risk; Safety; Sampling Errors; Sensitivity and Specificity; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Specificity; Staging; Systemic Therapy; Technology; Testing; Time; Tissues; Toxic effect; Toxicokinetics; Uveal Melanoma; Validation; X-Ray Computed Tomography; base; clinical care; clinical imaging; clinically significant; colorectal cancer metastasis; contrast enhanced; contrast imaging; crosslink; curative treatments; detection limit; early phase clinical trial; histological image; imaging approach; imaging capabilities; imaging modality; immunogenicity; improved; in vivo; innovation; liver imaging; metal poisoning; molecular array; molecular marker; mortality; mouse model; non-alcoholic fatty liver disease; novel; preclinical study; safety study; soft tissue; targeted agent; tumor; tumor heterogeneity; tumor microenvironment; tumor xenograft; ultrasound

PROJECT SUMMARY/ABSTRACT This SBIR application will develop an improved contrast agent for precision staging through early and accurate detection of pancreatic ductal adenocarcinoma (PDAC) liver metastasis. We have created an innovative platform technology using a new class of protein-based MRI contrast agents (ProCAs) for contrast-enhanced MRI. We have developed an effective approach to generate protein contrast agents against an array of molecular biomarkers including collagen I (ProCA32.collagen). This extracellular matrix protein is highly expressed in the tumor microenvironment and its expression levels and crosslinking increase upon progression. ProCA32.collagen exhibits 10- to 50-fold increase in both r1 and r2 relaxivities, compared to clinically-approved Gd3+ contrast agents, resulting in exceptional imaging capability that can discern heterogeneous tissue signals via a dual MR imaging methodology. ProCA32.collagen has strong collagen binding affinity, enables early detection of small liver metastases <0.2 mm and allows for mapping tumor heterogeneity in several murine xenograft tumor models; a 100-fold improvement in the detection limit over clinical contrast agents. ProCA32.collagen is expected to have a low risk related to metal toxicity due to its unprecedented metal binding selectivity and kinetic stability, prolonged blood retention and adequate biodistribution, which permits high quality imaging at low doses. This proposal will test the hypothesis that a non- invasive, in vivo MRI for accurate staging of PDAC through detection of subclinical liver metastases can be achieved by further optimizing the collagen targeted ProCA32.collagen+ contrast agent. This series of preclinical studies will provide data such as formulation and safety profile needed to submit an FDA Investigational New Drug (IND) application for an early phase clinical trial. This application will improve detection of subclinical metastasis and have broad impact for PDAC.

项目摘要/摘要 该SBIR应用将开发改进的对比剂，以通过早期和准确 检测胰腺导管腺癌（PDAC）肝转移。我们创建了一个创新平台 使用新的基于蛋白质的MRI对比剂（PROCA）进行对比增强MRI的技术。我们 已经开发了一种有效的方法来生成针对分子阵列的蛋白质对比剂 包括胶原蛋白I（Proca32.Collagen）在内的生物标志物。该细胞外基质蛋白在 肿瘤微环境及其表达水平和交联时增加 进展。 proca32.Collagen与R1和R2松弛性均表现出10至50倍 临床批准的GD3+对比剂，导致特殊的成像能力可以辨别 通过双重MR成像方法的异质组织信号。 Proca32.Collagen具有强胶原蛋白 结合亲和力，可以尽早检测小肝转移<0.2 mm并允许绘制肿瘤 几种鼠异种移植肿瘤模型中的异质性；检测极限改善100倍 临床对比剂。 Proca32.Collagen预计由于其金属毒性而具有低风险 前所未有的金属结合选择性和动力学稳定性，长时间保留和足够 生物分布，可以低剂量的高质量成像。该提议将检验以下假设 通过检测亚临床肝转移的侵入性，在体内MRI准确分期PDAC可以是 通过进一步优化的胶原蛋白靶向Proca32.Collagen+对比剂来实现。这个系列临床前 研究将提供数据，例如提交FDA调查新的新的配方和安全性概况 药物（IND）进行早期临床试验。该应用将改善亚临床的检测 转移，对PDAC产生广泛影响。