Dennis Kiyoshi Fujii

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.

A targeted contrast agent for magnetic resonance imaging of thrombus: Implications of spatial resolution

A preparation of ultra‐small superparamagnetic iron oxide (USPIO) particles coupled to an RGD peptide (RGD‐USPIO) was investigated as an MR contrast agent, targeted to activated platelets, in both ex vivo and in vivo thrombus models. Thrombus visualization ex vivo was compared using RGD‐USPIO and a non‐targeted UPSIO. The influence of thrombus visualization on thrombus exposure time to RGD‐USPIO (ex vivo) and on the spatial resolution of the MR image (ex vivo and in vivo) was assessed. RGD‐USPIO resulted in better thrombus visualization than non‐targeted USPIO ex vivo, and maximum enhancement was achieved after approximately one hour exposure time of the thrombus to RGD‐USPIO. The ability to visualize the clots was highly dependent on the spatial resolution of the image. In vivo, an in‐plane resolution of less than 0.2 × 0.2 mm2 was required for good clot visualization after contrast enhancement. It is concluded that the achievable resolution and sensitivity is a potential limitation to the usefulness of active vascular targeting in MRI. J. Magn. Reson. Imaging 2001;13:615–618.

‘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.

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.

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.