Jerome M. Lewis

Preclinical Safety and Pharmacokinetic Profile of Ferumoxtran-10, an Ultrasmall Superparamagnetic Iron Oxide Magnetic Resonance Contrast Agent

Objectives:This report presents an overview of preclinical data available on ferumoxtran-10, an ultrasmall superparamagnetic iron oxide nanoparticular contrast agent proposed for lymph node magnetic resonance imaging. Materials and Methods:Pharmacokinetic, safety pharmacology, single- and repeat-dose toxicity, reproduction toxicity, and genotoxicity studies were performed with ferumoxtran-10 given intravenously (bolus injection) in mice, rats, rabbits, dogs, and monkeys. Results:Ferumoxtran-10 was taken up by macrophages, mostly in liver, spleen, and lymph nodes, within 24 hours after bolus injection and underwent progressive metabolism. Toxicity was observed only at very high exposure levels and mainly was linked to a massive iron load after repeated injections. Ferumoxtran-10 was not mutagenic but was teratogenic in rats and rabbits. Discussion:The preclinical pharmacokinetic and safety profile of ferumoxtran-10 appears to be satisfactory in view of its proposed use as a single-dose diagnostic agent in human for MR imaging of lymph nodes.

Biologically degradable superparamagnetic materials for use in clinical applications

This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subjects hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.

A functionalized superparamagnetic iron oxide colloid as a receptor directed MR contrast agent

We have synthesized a surface functionalized superparamagnetic iron oxide colloid whose clearance from the vascular compartment was inhibited by asialofetuin but not fetuin. Unlike other particulate or colloidal magnetic resonance (MR) contrast agents, the agent of the current communication is not withdrawn from the vascular compartment by cells of the macrophage-monocyte phagocytic system, as indicated by its selective increase in hepatic relaxation rates. Because of this we refer to this colloid as a hepatic selective (HS) MR contrast agent. At 20 mumol Fe/kg the HS MR agent darkened MR images of liver. The HS MR agent exhibited no acute toxicity when injected into rats at 1800 mumol Fe/kg. Based on these observations, surface functionalized superparamagnetic iron oxide colloids may be the basis of MR contrast agents internalized by receptor mediated endocytosis generally, and by the asialoglycoprotein receptor in particular.

MR imaging of murine arthritis using ultrasmall superparamagnetic iron oxide particles

The objective of this work was to determine the ability of magnetic resonance (MR) imaging with ultrasmall superparamagnetic iron oxide (USPIO) particles to provide quantitative measures of inflammation in autoimmune arthritis. Mice were injected intravenously or intra-articularly with USPIO followed by magnetic resonance and histological assessment of the knee joint. Comparisons were made between MR microimages and histology in naïve mice and mice with collagen-induced arthritis.Following intravenous administration, accumulation of USPIO was observed in the popliteal lymph nodes, but not the joint. Administration of USPIO intra-articularly resulted in signal loss in the joint. The MR signal intensity could be quantified and correlated with iron staining in the synovial lining. A marked increase in USPIO uptake and a corresponding decrease in signal intensity were observed in arthritic, compared to naïve mice. Areas of focal signal loss corresponded to foci of iron staining by histology. These studies may provide a basis for the clinical application of USPIO in arthritis for assessing disease severity and monitoring response to therapy.

Biodegradable superparamagnetic metal oxides as contrast agents for MR imaging

This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subjects hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.

Use of USPIO-induced magnetic susceptibility artifacts to identity sentinel lymph nodes and lymphatic drainage patterns. I. dependence of artifact size with subcutaneous Combidex® dose in rats

Subcutaneously administered Combidex contrast agent produced characteristic magnetic susceptibility artifacts in gradient-echo (GE) images of rat brachial and axillary lymph nodes. These artifacts were useful in the rapid location and identification of normal sentinel lymph nodes. A linear dose response was observed with maximum artifact size in transverse images and was used noninvasively to study lymphatic drainage patterns.

Visualization of superior mesenteric lymph nodes by the combined oral and intravenous administration of the ultrasmall superparamagnetic iron oxide, AMI-227

Superior mesentric lymph nodes which lie as a chain near the small intestine are difficult to visualize in the rat with MRI either with or without the use of contrast agents. We previously demonstrated that the oral administration of an ultrasmall superparamagnetic iron oxide (AMI-227) produces a brightening of the lumen of the GI tract with a T1-weighted spin-echo pulse sequence. We have also shown that AMI-227 darkens abdominal lymph nodes. In the present study we show that the combined oral and intravenous administration of AMI-227 produces a brightening of the lumen of the GI tract and a darkening of the superior mesenteric lymph node chain. As a result of these combined and opposing effects on image signal intensity, a necessary contrast is established to reliably locate the superior mesenteric lymph nodes in vivo, which, to our knowledge, have been elusive by other techniques.

Use of AMI-227 as an oral MR contrast agent.

We report the use of an ultrasmall superparamagnetic iron oxide colloid AMI-227 as an oral contrast agent. Due to the small size, AMI-227 has a larger effect on T1 than larger superparamagnetic iron oxides colloids like ferumoxsil. At 2 T, AMI-227 had an R2/R1 of 11.4 compared with an R2/R1 for the superparamagnetic iron oxide ferumoxsil of 179. The R1s of the two agents were 7.1 and 1.6 mM-1 s-1, for AMI-227 and ferumoxsil, respectively. Due to its smaller R2/R1, orally administered AMI-227 can produce brightening or darkening of the lumen of the GI tract, depending on instrument parameters. At 1 mM Fe, image brightening (2 T, TR = 300, TE = 25) or image darkening of the GI tract (2 T, TR = 1500, TE = 80) was obtained. The ability of AMI-227 to produce either image brightening or darkening suggests it may be useful as an MR contrast agent for the GI tract.