Theoretical MRI contrast model for exogenous T₂ agents

Abstract

The rational development of new generations of MRI contrast agents (CAs) requires a scheme for predicting contrast enhancement. Previous contrast predictions have been based largely on empirical results in specific systems. Here we present a general theoretical model for evaluating the minimum concentration of T 2 CA required for satisfactory image contrast. This analytic contrast model is applicable to a wide range of T 2 -type agents and delivery scenarios, and requires only a few readily evaluated parameters. We demonstrated the model by predicting contrast produced by superparamagnetic ferumoxide and the iron storage protein, ferritin. We then experimentally verified the predictions using suspensions of Feridexா and ferritin in phantoms. The model was also used to compare the contrast efficacy of the metal ions in two clinically approved T 1 -and T 2 -type CAs. In the Appendix we present a numerical formalism that is useful for relating image contrast and agent concentration when gradient-echo (GRE) T* 2 -weighted (T There is great interest in developing new generations of MRI contrast agents (CAs) that can be used for diagnostic purposes, therapeutic monitoring, and to further our understanding of diseases. New generations of agents can often provide MRI contrast for specific cell types, detect the presence of specific molecules, such as enzymes and nucleic acids (1-3), and be responsive to physiology.Superparamagnetic iron oxide (SPIO) CAs are widely used as a platform for many of these emerging cellularmolecular applications (1). SPIO agents typically consist of an iron-oxide nanocrystal that is coated with dextran or polymer and have a net median diameter of 10 -100 nm. SPIO particles perturb the static magnetic field out to a distance on the order of ϳ50 2 times its diameter, resulting in a dramatic reduction in T 2 of nearby water molecules. The resulting images exhibit hypointense regions, indicating agent accumulation. Unmodified SPIO particles, such as Resovist, Feridex, and Combidex, have been used for cellular imaging (4) and are FDA-approved for detecting liver lesions and distinguishing between normal and cancerous lymph nodes. SPIO particles with surfaces conjugated to targeting entities, such as peptides or antibodies, have also been described (4). Intracellular applications of SPIO for cell-tracking in animal models is a rapidly evolving research area (5), and the clinical translation of these techniques is already in the early stage (6).In addition, T 2 -type CAs are included in a new category of intracellular labeling approaches that utilize genetically-encoded metalloproteins (2,7). In this approach, metalloproteins from the ferritin family are expressed in specific host tissues. These iron-storage metalloproteins effectively become a superparamagnetic CA by sequestering endogenous iron from the organism and thus imparting MRI contrast to targeted tissues.For useful images to be generated, CAs must accumulate in cells or tissues in adequate concentrations. Moreover, too high of a concentra...

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“…MRI has a significantly higher spatial resolution (µm) than radiodiagnostic techniques (mm), but its use as a tool for the investigation of cellular molecular events in normal and pathological processes is hampered by its low sensitivity: a relatively large local concentration of CA is required (about 10 -5 M) to achieve the desired contrast enhancement. 2,3 Other imaging modalities such as PET, SPECT (10 -11 -10 -12 M), and optical fluorescence imaging (10 -15 -10 -17 M) are much more adequate in this respect. 4 A possible approach to overcome the problems related with the low sensitivity of MRI is to apply vectorized CAs, which would bring a high payload of paramagnetic compound to the site of interest.…”