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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.

项目摘要/摘要