Liver Specific Manganese Based MRI Contrast Agent

肝脏专用锰基 MRI 造影剂

基本信息

批准号：
10247834
负责人：
Vera Hoffman
金额：
$ 99.93万
依托单位：
REVEAL PHARMA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247834
关键词：
Address Authorization documentation Benign Binding Proteins Biological Assay Blood Breast Cancer Etiology Cancer Model Cardiotoxicity Cells Cessation of life Chelating Agents Chemicals Chromatography Clinical Colorectal Complex Contrast Media Cyclic GMP Development Diagnosis Diethylnitrosamine Differential Diagnosis Disease Dose Drug Kinetics Early Diagnosis Elements European Extracellular Fluid Focal Nodular Hyperplasia Frequencies Gadolinium Gadolinium DTPA General Hospitals Gold Hepatocyte Histologic Hour Human Human body Hypervascular Image Immune In Vitro Injections Ions Knock-in Mouse Lesion Libraries Liver Liver diseases Liver neoplasms Liver parenchyma Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of liver Manganese Manufacturer Name Marketing Massachusetts Maximum Tolerated Dose Measures Medicine Metabolism Metastatic Neoplasm to the Liver Microsomes Modeling Neoplasm Metastasis Noise Nutritional Organic Anion Transporters Oryctolagus cuniculus Patients Pentetic Acid Peptides Pharmacologic Substance Phase Plasma Proteins Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Property Protocols documentation Radiology Specialty Rattus Reaction Rifampin Safety Screening for Hepatocellular Cancer Series Structure Structure-Activity Relationship Technology Technology Transfer Toxic effect Toxicokinetics base candidate selection clinical translation contrast imaging cost effective extracellular genotoxicity high risk in vivo lead candidate lead optimization lipophilicity liver imaging melanoma mortality preclinical development standard of care toxic metal tumor uptake

项目摘要

Project Summary / Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and HCC mortality is increasing at a faster rate than any other cancer. Metastatic liver disease occurs with greater frequency than HCC and is also associated with high mortality rates. There is a significant survival benefit associated with early detection of liver tumors. However, the liver-specific gadolinium (Gd)-based MRI contrast agents (GBCAs) which are the radiologic standard of care for diagnoses of liver malignances do not optimally meet clinical needs and have come under intense regulatory scrutiny over concerns of Gd retention and delayed Gd-associated toxicity. The two GBCAs used for liver imaging, Gd-EOB-DTPA and Gd-BOPTA, belong to the class of GBCAs comprised of acyclic chelators, which are associated with the highest risk of Gd release. The European Medicines Agency suspended the marketing authorizations for the 3 acyclic extracellular fluid GBCAs, but allowed the GBCAs used for liver specific imaging to remain available for restricted use in liver scans because these agents satisfy the need for diagnosis of liver cancer and metastatic liver disease. Gd-EOB-DTPA and Gd- BOPTA provide initial dynamic phase enhancement of hypervascular structures, and subsequently accumulate in hepatocytes via the action of organic anion transporter peptides (OATPs) resulting in hepatocellular enhancement on delayed phase imaging. The different contrasts observed in lesions during dynamic and delayed phase imaging enable differential diagnosis of liver malignancies from common, benign abnormalities. However, the dynamic enhancement of delayed phase lesions is poor with Gd-EOB-DTPA compared to Gd- BOPTA, but the delayed phase enhancement with Gd-BOPTA is lower than with Gd-EOB- DTPA and is performed 1 hour post injection, limiting patient throughput. Our solution to these problems is to develop a Gd- free liver-specific contrast agent with optimized dynamic and delayed phase contrast properties. Reveal Pharmaceuticals has demonstrated that the extracellular manganese (Mn)-based contrast agent RVP-001 (aka Mn-PyC3A) provides equivalent extracellular contrast to GBCAs, does not release free Mn2+ ion, and is more effectively eliminated from the body than GBCAs. In this FastTrack application we will develop OATP-targeted contrast agents that utilize the chemically stable, high relaxivity Mn-PyC3A core for liver specific imaging. In Phase I we will identify a lead candidate and demonstrate strong, conspicuous enhancement of liver tumors in humanized OATP knock-in mice. In Phase II we will perform lead optimization with respect to relaxivity, pharmacokinetics, safety, and liver image contrast, and select a development candidate (DC) for ultimate clinical translation. We will validate our DC in rat and rabbit models of liver cancer, and evaluate its safety in rats. We will develop a scalable, cost effective synthesis of the DC for technology transfer to a cGMP manufacturer.

项目概要/摘要肝细胞癌 (HCC) 是全球第二大癌症死亡原因，HCC 死亡率的增加速度比任何其他癌症都快。转移性肝病的发生率更高其发生率高于 HCC，并且还与高死亡率相关。有显着的生存效益与肝脏肿瘤的早期发现有关。然而，肝脏特异性钆 (Gd) MRI 对比作为诊断肝脏恶性肿瘤的放射学护理标准的药物（GBCA）并不能达到最佳效果满足临床需求，并因 Gd 保留和延迟的担忧而受到严格的监管审查与 Gd 相关的毒性。用于肝脏成像的两种 GBCA，Gd-EOB-DTPA 和 Gd-BOPTA，属于由无环螯合剂组成的 GBCA 类，与最高的 Gd 释放风险相关。这欧洲药品管理局暂停了 3 种无环细胞外液 GBCA 的营销授权，但允许用于肝脏特异性成像的 GBCA 仍可在肝脏扫描中有限使用，因为这些试剂满足了肝癌和转移性肝病诊断的需要。 Gd-EOB-DTPA 和 Gd- BOPTA 提供富血管结构的初始动态阶段增强，并随后积累通过有机阴离子转运肽（OATP）的作用在肝细胞中产生肝细胞延迟相位成像的增强。动态和动态期间在病变中观察到的不同对比度延迟相位成像能够区分肝脏恶性肿瘤和常见的良性异常。然而，与 Gd-EOB-DTPA 相比，Gd-EOB-DTPA 对延迟期病灶的动态增强较差。 BOPTA，但 Gd-BOPTA 的延迟相位增强低于 Gd-EOB-DTPA，并且注射后 1 小时进行，限制了患者的处理量。我们解决这些问题的方法是开发一个 Gd- 具有优化动态和延迟相差特性的免费肝脏特异性造影剂。揭示 Pharmaceuticals 已证明细胞外锰 (Mn) 基造影剂 RVP-001（又名 Mn-PyC3A) 提供与 GBCA 相当的细胞外对比度，不释放游离 Mn2+ 离子，并且更比 GBCA 更能有效地从体内消除。在此 FastTrack 应用程序中，我们将开发以 OATP 为目标的利用化学稳定、高弛豫率 Mn-PyC3A 核心进行肝脏特异性成像的造影剂。在在第一阶段，我们将确定一个主要候选者，并证明肝脏肿瘤的强烈、显着增强。人源化 OATP 敲入小鼠。在第二阶段，我们将针对弛豫度进行先导优化，药代动力学、安全性和肝脏图像对比，并选择最终临床的开发候选者（DC）翻译。我们将在大鼠和兔肝癌模型中验证我们的 DC，并评估其在大鼠中的安全性。我们将开发一种可扩展、具有成本效益的 DC 合成方法，以便将技术转让给 cGMP 制造商。