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.
Public Health Relevance Statement: Project Narrative Liver cancer is the second most common cause of cancer death worldwide and the frequency of liver cancer mortality is increasing at a faster rate than another other cancer. Other common cancers (breast, colorectal, melanoma) also metastasize to the liver. Current liver-specific MRI contrast agents have high sensitivity to detect disease but have technical limitations and all utilize the toxic metal ion gadolinium. This FastTrack application focuses on addressing this need by creating a technically superior liver-specific contrast agent that does not contain gadolinium.
NIH Spending Category: Biomedical Imaging; Cancer; Digestive Diseases; Liver Cancer; Liver Disease; Orphan Drug; Rare Diseases
Project Terms: Address; Authorization documentation; base; Benign; Binding Proteins; Biological Assay; Blood; Breast; Cancer Etiology; Cancer Model; candidate selection; Cardiotoxicity; Cells; Cessation of life; Chelating Agents; Chemicals; Chromatography; Clinical; clinical translation; Colorectal; Complex; contrast imaging; Contrast Media; cost effective; Cyclic GMP; Development; Diagnosis; Diethylnitrosamine; Differential Diagnosis; Disease; Dose; Drug Kinetics; Early Diagnosis; Elements; European; extracellular; Extracellular Fluid; Focal Nodular Hyperplasia; Frequencies; Gadolinium; Gadolinium DTPA; General Hospitals; genotoxicity; Gold; Hepatocyte; high risk; Histologic; Hour; Human; Human body; Hypervascular; Image; Immune; In Vitro; in vivo; Injections; Ions; Knock-in Mouse; lead candidate; lead optimization; Lesion; Libraries; lipophilicity; Liver; Liver diseases; liver imaging; Liver neoplasms; Liver parenchyma; Magnetic Resonance Imaging; Malignant neoplasm of liver; Malignant Neoplasms; Manganese; Manufacturer Name; Marketing; Massachusetts; Maximum Tolerated Dose; Measures; Medicine; melanoma; Metabolism; Metastatic Neoplasm to the Liver; Microsomes; Modeling; mortality; Neoplasm Metastasis; Noise; Nutritional; Organic Anion Transporters; Oryctolagus cuniculus; Patients; Pentetic Acid; Peptides; Pharmacologic Substance; Phase; Plasma Proteins; preclinical development; Primary carcinoma of the liver cells; Primary Malignant Neoplasm of Liver; Property; Protocols documentation; Radiology Specialty; Rattus; Reaction; Rifampin; Safety; Screening for Hepatocellular Cancer; Series; standard of care; Structure; Structure-Activity Relationship; Technology; Technology Transfer; Toxic effect; toxic metal; Toxicokinetics; tumor; uptake
