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.

项目概要/摘要 该 SBIR 应用将开发一种改进的造影剂，用于通过早期和准确的精确分期 检测胰腺导管腺癌（PDAC）肝转移。我们创建了一个创新平台 使用新型蛋白质 MRI 造影剂 (ProCA) 进行对比增强 MRI 的技术。我们 开发了一种有效的方法来生成针对一系列分子的蛋白质造影剂 生物标志物，包括胶原蛋白 I (ProCA32.collagen)。这种细胞外基质蛋白在 肿瘤微环境及其表达水平和交联增加 进展。与相比，ProCA32.collagen 的 r1 和 r2 松弛度均增加 10 至 50 倍 临床批准的 Gd3+ 造影剂，具有卓越的成像能力，可以辨别 通过双 MR 成像方法发出异质组织信号。 ProCA32.collagen 具有强效胶原蛋白 结合亲和力，能够早期检测 <0.2 毫米的小肝转移瘤，并能够绘制肿瘤图 几种小鼠异种移植肿瘤模型的异质性；检测限提高 100 倍 超过临床造影剂。 ProCA32.collagen 预计与金属毒性相关的风险较低，因为它 前所未有的金属结合选择性和动力学稳定性、延长的血液保留和足够的 生物分布，可在低剂量下实现高质量成像。该提案将检验以下假设：非 侵入性体内 MRI 通过检测亚临床肝转移来准确对 PDAC 进行分期 通过进一步优化胶原蛋白靶向 ProCA32.collagen+ 造影剂来实现。本系列临床前 研究将提供提交 FDA 研究报告所需的配方和安全概况等数据 早期临床试验的药物（IND）申请。该应用程序将改善亚临床的检测 转移并对 PDAC 产生广泛影响。