Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI

Morawski, Anne M.; Winter, Patrick M.; Crowder, Kathryn C.; Caruthers, Shelton D.; Fuhrhop, Ralph W.; Scott, Michael J.; Robertson, John; Abendschein, Dana R.; Lanza, Gregory M.; Wickline, Samuel A.

doi:10.1002/mrm.20010

Cited by 265 publications

(218 citation statements)

References 29 publications

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“…Thus, the imaging capability provided is not from the SPIO intrinsically, but through their influence on longitudinal and transverse relaxation of the surrounding nuclei. Although the ability of SPIO to significantly reduce the spin-spin relaxation (T2) time is generally relied on for generating MR contrast, 68,99 it has also been demonstrated that SPIO can generate sufficient T1 contrast for biomedical applications as well; SPIO possess both high R1 and R2 relaxivities. 118,127 Upon removal of the magnetic field, Brownian motion is sufficient to randomize the SPIO orientations leaving no magnetic remanence.…”

Section: Magnetismmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

et al. 2006

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Abstract-The field of molecular imaging has recently seen rapid advances in the development of novel contrast agents and the implementation of insightful approaches to monitor biological processes non-invasively. In particular, superparamagnetic iron oxide nanoparticles (SPIO) have demonstrated their utility as an important tool for enhancing magnetic resonance contrast, allowing researchers to monitor not only anatomical changes, but physiological and molecular changes as well. Applications have ranged from detecting inflammatory diseases via the accumulation of non-targeted SPIO in infiltrating macrophages to the specific identification of cell surface markers expressed on tumors. In this article, we attempt to illustrate the broad utility of SPIO in molecular imaging, including some of the recent developments, such as the transformation of SPIO into an activatable probe termed the magnetic relaxation switch.

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Section: Magnetismmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

et al. 2006

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“…[8] for ␣ by setting CNR ϭ 5 and performing a numerical fit (R 2 ϭ 0.99) for a realistic range of values (40 Ͻ Ͻ 600), which yields ␣ ϭ Ϫ 10.5 /͑1Ϫ ͒ ϩ 0.642 1/͑1Ϫ ͒ ϩ 0.36. [9] To generalize Eq. [9] for different values of CNR, substitute with NEW ϭ ͑5/CNR NEW ͒ .…”

Section: Theorymentioning

confidence: 99%

“…[9] To generalize Eq. [9] for different values of CNR, substitute with NEW ϭ ͑5/CNR NEW ͒ . Now, we allow Eq.…”

Section: Theorymentioning

confidence: 99%

Theoretical MRI contrast model for exogenous T₂ agents

Mills

Ahrens

2007

Magnetic Resonance in Med

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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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“…While not unreasonable in theory, the detection limit of a low MW targeted agent has not, to the best of our knowledge, been quantitatively tested in a simple model system. Most studies reporting quantitative detection levels of T 1 agents are based upon binding of a chelate to a soluble protein, total Gd 3+ taken into cells, or Gd 3+ -loaded nanoparticles with an affinity for cells [1,15,22,23]. For example, the limit of detection for simple Gd 3+ -chelates in cells has been reported to range from 10 7 -10 8 Gd 3+ -chelates per cell [15,22] which, for a cell diameter of 5 µm, corresponds to concentrations ranging from 130 µM to 1.3 mM.…”

Section: Introductionmentioning

confidence: 99%

“…For example, the limit of detection for simple Gd 3+ -chelates in cells has been reported to range from 10 7 -10 8 Gd 3+ -chelates per cell [15,22] which, for a cell diameter of 5 µm, corresponds to concentrations ranging from 130 µM to 1.3 mM. Molecular epitopes have been successfully targeted using ~250 nm diameter nanoparticles that contain > 90,000 Gd 3+ chelates/particle [23] although this report did not indicate the concentration of the receptors that could be detected. Although the concentration of the nanoparticles at the estimated detection limit was reported as 113 pM, this corresponds to a Gd 3+ concentration of 10 µM.…”

Section: Introductionmentioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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Simple low MW chelates of Gd 3+ such as those currently used in clinical MR imaging are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit of a molecularly targeted, low MW Gd 3+ -based, T 1 agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T 1 weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K D = 150 nM) for the antibody while the fully bound relaxivity of the GdDO3A-peptide:anti-FLAG antibody in solution was a relatively modest 17 mM −1 s −1 . The agent:antibody complex was MR silent at concentrations below ~9 µM but was detectable down to 4 µM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the detection limits for other T 1 -based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly-targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented which predicts that for a molecularly targeted agent consisting of a single Gd 3+ complex with bound relaxivity of 100 mM −1 s −1 or, more reasonably, four tethered Gd 3+ complexes each having a bound relaxivity of 25 mM −1 s −1 , the detection limit of a protein microdomain is ~690 nM at 9.4T. These experimental and extrapolated detection limits are both well below current literature estimates and suggests that detection of low MW molecularly targeted T 1 agents is not an unrealistic goal.

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Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI

Cited by 265 publications

References 29 publications

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

Theoretical MRI contrast model for exogenous T₂ agents

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

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Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI

Cited by 265 publications

References 29 publications

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

Theoretical MRI contrast model for exogenous T2 agents

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

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Theoretical MRI contrast model for exogenous T₂ agents