Kenneth E. Kellar

NC100150 injection, a preparation of optimized iron oxide nanoparticles for positive-contrast MR angiography

A preparation of monocrystalline iron oxide nanoparticles with an oxidized starch coating, currently in clinical trials (NC100150 Injection; CLARISCAN™), was characterized by magnetization measurements, relaxometry, and photon correlation spectroscopy. By combining the results with a measure of iron content, one can obtain the size and magnetic attributes of the iron cores, including the relevant correlation times for outer sphere relaxation (τSO and τD), and information about the interaction of the organic coating with both core and solvent. The results are 6.43 nm for the iron oxide core diameter, a magnetic moment of 4.38 × 10−17 erg/G, and a water‐penetrable coating region of oxidized oligomeric starch fragments and entrained water molecules. The latter extends the hydrodynamic diameter to 11.9 nm and lowers the average diffusivity of solvent about 64% (which increases τD accordingly). The nanoparticles show little size‐polydispersity, evidenced by the lowest value of r2/r1 at 20 MHz reported to date, an asset for magnetic resonance angiography. J. Magn. Reson. Imaging 2000;11:488–494.

Polymeric gadolinium chelate magnetic resonance imaging contrast agents: design, synthesis, and properties.

We have synthesized and evaluated five series of polymeric gadolinium chelates which are of interest as potential MRI blood pool contrast agents. The polymers were designed so that important physical properties including molecular weight, relaxivity, metal content, viscosity, and chelate stability could be varied. We have shown that, by selecting polymers of the appropriate MW, extended blood pool retention can be achieved. In addition, relaxivity can be manipulated by changing the polymer rigidity, metal content affected by monomer selection, viscosity by polymer shape, and chelate stability by chelator selection.

‘NC100150’, a preparation of iron oxide nanoparticles ideal for positive-contrast MR angiography

A laboratory-scale synthesis of NC100150 (iron oxide particles with an oxidized starch coating) was characterized by magnetization measurements (vibrating sample magnetometry, VSM), relaxometry (1/T1 NMRD profiles and 1/T2 at 10 and 20 MHz), and dynamic light scattering (photon correlation spectroscopy, PCS). The results were related to give a self-consistent physical description of the particles: a water-impenetrable part making up 12% of the total particle volume, 82% of this volume consisting of an iron oxide core and the remaining 18% consisting of an oxidized starch rind; and, a water-penetrable part making up 88% of the total particle volume, consisting of oxidized starch polymers and entrained water molecules. Relating the magnetization to the relaxometry results required that the oxidized starch coating slows the diffusivity of solvent water molecules in the vicinity of the iron oxide cores. The effect of the organic coating on water diffusivity, not previously considered in the application of relaxation theory to iron oxide nanoparticles, is supported by the much greater (factor of about 2) diameter obtained from the dynamic light scattering measurements in comparison to that obtained from the magnetization measurements. The present work shows that three physical techniques—VSM, relaxometry, and PCS—are needed for properly assessing iron oxide nanoparticles for use as contrast agents for magnetic resonance angiography (MRA). It is also shown that NC100150 has a narrow range of diameters and the smallest value ofr2/r1 reported to date, an asset for MRA.

Gadolinium-based linear polymer with temperature-independent proton relaxivities: a unique interplay between the water exchange and rotational contributions†‡

Macromolecular complexes of Gd(III) chelates are widely investigated as MRI contrast agents. In addition to the potential increase in relaxivity, they have a further advantage over the Gd(III) chelates of an extended lifetime in the blood pool, which is necessary for magnetic resonance angiography applications. When designing macromolecular complexes of Gd(III) chelates, it is important to know how the parameters that determine relaxivity are affected in comparison with those of the chelate. This paper reports variable‐temperature EPR, variable‐temperature and ‐pressure, multiple field 17O NMR and variable‐temperature NMRD studies on a linear Gd(DTPA–bisamide)–poly(ethylene glycol) copolymer. The rate [kex298=(4.8±0.1)×105 s‐1] and mechanism (dissociatively activated) of the water exchange are identical with those on the corresponding chelate. The rotational correlation time (τR=232 ps) is not much longer than that of the monomer unit restricted to rotate around a single axis, indicating large flexibility of the ethylene glycol chain. The proton relaxivities of the linear polymer complex are virtually independent of temperature, a result of an offset between the opposite dependences of the outer‐ and inner‐sphere contributions with temperature. ©1998 John Wiley & Sons, Ltd.

Investigation of lanthanide-based starch particles as a model system for liver contrast agents.

Gadolinium and dysprosium diethylenetriamine pentaacetic acid‐labeled starch microparticles (Gd‐DTPA‐SP and Dy‐DTPA‐SP) were investigated as model liver contrast agents. The liver contrast efficacy of particles with low and high metal contents was compared in two imaging models: in vivo rat liver and ex vivo perfused rat liver. The biodistribution of intravenously injected particles was also assessed by ex vivo relaxometry and inductively coupled plasma atomic emission spectrophotometry of tissues. All particles reduced the liver signal intensity on T2‐weighted spin‐echo and gradient‐recalled echo images as a result of susceptibility effects. Because of their higher magnetic susceptibility, the Dy‐DTPA‐SP were more effective negative contrast enhancers than the Gd‐DTPA‐SP. On T1‐weighted spin‐echo images, only the Gd‐DTPA‐SP with low metal content significantly increased the liver signal intensity. In addition, these low‐loading Gd‐DTPA‐SP markedly reduced the blood T1. The two latter observations were not consistent with the anticipated blood circulation time of microparticles, but were a result of the lower stability of these particles in blood compared with Gd‐DTPA‐SP, which has a high metal content. Regardless of stability or imaging conditions, the paramagnetic starch particles investigated showed potential as negative liver contrast enhancers. However, the observed accumulation of particles in the lungs represented a biological limitation for their use as contrast agents.J. Magn. Reson. Imaging 1999; 9:295–303.

Effect of NC100150 injection on the 1H NMR linewidth of human whole blood ex vivo: Dependency on blood oxygen tension

The linewidth of the 1H NMR signal (7.05 T) of human whole blood titrated with a superparamagnetic contrast agent (NC100150 injection) was evaluated at different blood oxygen tensions. In deoxygenated blood and low contrast agent concentrations, NC100150 injection caused a decrease in linewidth. After reaching a minimum, the linewidth increased as the concentration of NC100150 injection increased. At the concentration corresponding to the minimum linewidth, the magnetization of the extracellular space containing the NC100150 injection was equal to that of the paramagnetic (deoxygenated hemoglobin) intracellular space. The minimum linewidth is therefore consistent with a complete elimination of the local microscopic susceptibility effect, the major cause of linebroadening. Additionally, phantom studies were performed at 1.5 T, confirming that the contrast enhancement of NC100150 injection in blood is dependent on oxygen tension. The data suggest that NC100150 injection may be useful in differentiating vessels with varying relative oxygen tensions. Magn Reson Med 44:803–807, 2000.

Important considerations in the design of iron oxide nanoparticles as contrast agents for Tl-weighted MRI and MRA

Organically coated magnetic monocrystalline iron oxide nanoparticles are being considered as contrast agents for T1-weighted magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) (1–4). For such Tl-weighted applications, imaging efficacy is strongly dependent on the physical characteristics of the individual nanoparticles (5). In particular, three stringent physical requirements must be satisfied. First, the magnetic cores must be of an optimal size with essentially a monodisperse size distribution. If the cores are too small, rl (the Tl relaxivity) will be too small for practical applications as T1 agents; if the cores are too large, r2 (the T2 relaxivity) may be so large relative to rl that the T1 efficacy of the particles will be diminished. Second, the high-field magnetization of the cores, typically close to its saturation value, must be sufficient to relax water protons effectively, also implying that the organic coating must not compromise access of solvent to the core. This high-field limit is related to both the total iron content of the cores and their geometry. Third, the nanoparticles cannot become agglomerated in vivo. Given that r2 is very sensitive to agglomeration and rl is not, agglomeration preferentially increases r2, thereby diminishing the efficacy of the nanoparticles as Tl agents. In the current work, the relative physical characteristics of two distinct nanoparticle preparations are compared with respect to their efficacy for Tl-weighted MRI and MRA: MION-46L and NC100150 Injection. 1/Tl nuclear magnetic relaxation dispersion (NMRD) profiles suffice for such a comparison, and magnetization data (as discussed by Koenig et al [6] in this supplement) are not needed.

Low-molecular weight lanthanide contrast agents: Evaluation of susceptibility and dipolar effects in red blood cell suspensions

Red blood cell (RBC) suspensions, containing low-molecular weight (LMW) dysprosium (Dy) and gadolinium (Gd) chelates, were selected as a two-compartment system for the evaluation of the magnetic dipolar and susceptibility contributions to the transverse (T2) relaxation of solvent water protons. The influence of RBC geometry and degree of metal chelate compartmentalization on T2 was investigated by variation of the osmolality and hematocrit (HC), respectively. The T2-relaxation ability of Dy-chelates was markedly improved in RBC suspensions, in comparison to aqueous solutions, due to the presence of susceptibility effects that more than compensated for the low dipolar relaxation efficacy. Despite a smaller susceptibility effect, the Gd-chelates were still the most efficacious in shortening T2 due to their comparatively larger dipolar relaxation contribution. The results obtained with the Dy-chelates allowed the evaluation of the relative contributions of susceptibility and dipolar mediated relaxation for the Gd-chelates. The RBC geometry and degree of compartmentalization influenced strongly the T2 relaxation efficacy of Dy-chelates, as opposed to the Gd-chelates. Hemolysis eliminated the susceptibility effect, essentially removing the T2 relaxation ability of Dy-chelates. The T2 relaxation efficacy of Gd-chelates was improved by hemolysis due to enhancement of the dipolar relaxation. As a conclusion, RBC suspensions have clearly been shown to be a suitable ex vivo model with which to distinguish the different contrast mechanisms of LMW Dy- and Gd-based MRI contrast agents.

Three Types of Physical Measurements Needed to Characterize Iron Oxide Nanoparticles for MRI and MRA: Magnetization, Relaxometry, and Light Scattering

Iron oxide nanoparticles, with monocrystalline cores (generally magnetite or maghemite) and coated with organic polymer to increase chemical stability and solubility, have generated widespread interest as negative contrast (susceptibility) agents for magnetic resonance imaging (MRI) (1,2). For negative agents, the requisite T2 shortening depends on the geometry of the physiologic structures that take up the agent (2) but is relatively insensitive to the size and structure of the nanoparticles themselves. Nanoparticles also have a potential as positive agents for magnetic resonance angiography (MRA) (3–6), an application that depends on T1 shortening in the vasculature by individual nanoparticles, provided that T2 is not too short (7). To optimize their suitability for MRA, the agents must be synthesized and characterized reproducibly, the size of the magnetic core must be carefully controlled, and the interaction of the organic coating with nearby solvent molecules must be understood (8). Here we describe a set of physical techniques for measuring the parameters that determine MRA efficacy: the magnetic moment and diameter d of the iron oxide cores, and the interaction of organic coating with solvent. We study magnetization (8) as a function of magnetic field B0; l/Tl nuclear magnetic relaxation dispersion (NMRD) profiles (9) for B0 from 0.24 mT to 1.2 T (0.01–50 MHz) and 1/T2 at 0.47 T (20 MHz); and solute translational diffusivity by photon correlation spectroscopy (PCS) (10). As demonstrated earlier (8), magnetization data, being thermodynamic, yield and the saturation magnetization of the particles, Msat. Combined with total iron content and the known density of the core, one obtains d. When these results are combined with NMRD data—which depend on and d and yield certain correlation times—one can detect any water-opaque organic “rind” and measure the diffusivity D of outer sphere solvent, a measure of viscous interactions between solvent and polymer. These interactions can be quantitated by PCS, which yields the effective radius of gyration of the polymers (11), including contributions from both polymer and viscously entrained water molecules. This trio of measurements lets one characterize the physical properties of solute nanoparticles self-consistently, deduce their behavior in MRA applications, and guide the development of improved agents. We report on two preparations of coated iron oxide nanoparticles: (a) CLARISCAN, a Nycomed Amersham product in clinical trials (8); and (b) MION-46L, a laboratory preparation (11) of MION-46 obtained from Massachusetts General Hospital.

Blood-Pool contrast agents for MRI: A critical evaluation

Blood-pool contrast agents in current use in clinical MRI are, in the main, small, highly stable, Gd3+-chelate complexes with a single inner-coordinated water molecule on the metal ion. Unfortunately, their relaxivities, and hence efficacy, diminish as the strength of the imaging field B 0 increases above -0.1 T, an effect associated with their rapid thermal rotation in solution (1). Restricting this rotation, for example, by rigid attachment of the small paramagnetic moiety to a macromolecule, can increase the relaxivity 10-fold in the 0.5-1.5-T range. The underlying physical mechanisms have been understood for several decades (2), and a quantitative comparison of the relaxivities expected for Gd(DTPA) 2and Gd(DOTA) 1bound to serum albumin, from theory, has been given in an earlier CMR symposium (3). There is, in addition, a range of relatively early experimental results that demonstrate the predicted enhancements, including measurements of solutions of binary complexes of Gd 3+ ions with macromolecules and ternary complexes that involve ligands such as DTPA. But what is of particular interest is the variety of approaches being pursued currently: covalent complexes of Gd(DTPA) 2with serum albumin (4); hydrophobic association of Gd(DTPA) 2derivatives with albumin (5-7); polymers of Gd(DTPA)2--containing monomers (8); attachment of Gd(DTPA) 2--, by a lipid tail, to phospholipid