Morphological Analysis of Reticuloendothelial System in Capuchin Monkeys (Sapajus spp.) after Meso-2,3-Dimercaptosuccinic Acid (DMSA) Coated Magnetic Nanoparticles Administration.

Magnetic nanoparticles can be used for numerous in vitro and in vivo applications. However, since uptake by the reticuloendothelial system represents an obstacle for the achievement of nanoparticle diagnostic and therapeutic goals, the aim of the present study was to evaluate the uptake of dimercaptosuccinic acid coated magnetic nanoparticles by reticuloendothelial system phagocytic cells present in lymph nodes, spleen, and liver tissue and how the presence of these particles could have an impact on the morphology of these organs in capuchin monkeys (Sapajus spp.). Animals were intravenously injected with dimercaptosuccinic acid coated magnetic nanoparticles and euthanized 12 hours and 90 days post-injection. Organs were processed by transmission electron microscopy and histological techniques. Samples of spleen and lymph nodes showed no morphological changes. Nevertheless, liver samples collected 90 days post-administration showed slight morphological alteration in space of Disse. Moreover, morphometrical analysis of hepatic mitochondria was performed, suggesting a clear positive correlation between mitochondrial area and dimercaptosuccinic acid coated magnetic nanoparticles administration time. The present results are directly relevant to current safety considerations in clinical diagnostic and therapeutic uses of magnetic nanoparticles.

RES-specific imaging of the liver and spleen with iron oxide particles designed for blood pool MR-angiography.

The purpose of this study was to determine the dependency of liver- and spleen-enhancement on particle size and dose of bolus-injectable iron oxides designed for blood-pool MR-angiography (MRA). The superparamagnetic iron oxide SHU 555 A [particle size 65 nm (group 1)] and three derivatives designed for blood-pool MRA (groups 2-4) with smaller hydrodynamic diameters (46/33/21 nm) were i.v. injected in New Zealand White rabbits at doses of 10, 20, or 40 micromol Fe/kg bw. MRI was performed before, 2, and 24 hours after contrast application using T1-weighted SE and T2-weighted TSE sequences. In addition splenic tissue was harvested post mortem and scanned ex vivo. All iron oxides significantly decreased the SI of liver and spleen in T1- and T2-weighted images at 2 and 24 hours after application of contrast media (P < 0.01). The signal intensity was inversely related to the dose applied. Decreasing particle size resulted in a lower signal enhancement in liver and spleen. However, ultra-small superparamagnetic iron oxides suited for blood-pool MRA (USPIOs, group 4) still revealed a significant signal enhancement in the liver and spleen even 24 hours after contrast application (< - 60%, 40 micromol Fe/kg bw). They might thus be used for comprehensive abdominal studies including contrast enhanced MR-angiography and RES-specific imaging.

New MR imaging contrast agents.

Many new MR contrast agents are undergoing laboratory development, are in clinical trials, or are being used for routine clinical applications. These agents function by targeting specific receptors that allow the agent to accumulate within the reticuloendothelial system, the hepatobiliary system, or the blood pool. Each agent has unique properties that offer advantages over unenhanced and gadolinium chelate-enhanced MR imaging. Use of these agents, however, requires an understanding of their current and potential clinical indications and inherent limitations. This article reviews the development, evaluation, and clinical application of a number of these agents, including ferumoxides, Mn-DPDP, AMI-227, SHU-555A, Gd-EOB/DTPA, Gd-BOPTA, and MS-325.

Sonochemically produced fluorocarbon microspheres: a new class of magnetic resonance imaging agent.

With the intent of increasing the signal-to-noise ratio (SNR) of fluorine magnetic resonance imaging and enabling new applications, we have developed a novel class of agents based on protein encapsulation of fluorocarbons. Microspheres formed by high-intensity ultrasound have a gaussian size distribution with an average diameter of 2.5 microns. As with conventional emulsions, these microspheres target the reticuloendothelial system. However, our sonochemically produced microspheres, because of a high encapsulation efficiency, show increases in the SNR of up to 300% compared to commercially available emulsions. We also demonstrate an increase in the circulation lifetime of the microspheres with the bloodstream by more than 30-fold with a chemical modification of the outer surface of the microsphere. Finally, by encapsulating mixtures of fluorocarbons that undergo solid/liquid phase transitions, we can map temperature in the reticuloendothelial system, with signal changes of approximately 20-fold over a 5 degrees C range.

19F magnetic resonance imaging of the reticuloendothelial system.

In this study sequential 1H and 19F magnetic resonance imaging methods were used to map the distribution of fluorinated compounds in vivo. An intravenously administered emulsion of perfluorooctylbromide (PFOB), an agent known to localize in the reticuloendothelial system, was detected in the liver and spleen of all studied hamsters and mice using 19F MRI. Lungs and salivary glands were also affected in some animals. Using a G. E. NMR CSI 2-T spectroscopy/imaging system, projection 19F images were obtained in 4 to 8 min. Subsequent mouse studies using a thick-slice driven equilibrium pulse sequence produced 19F images with an improved signal-to-noise ratio in a shorter acquisition time. With PFOB, 19F MRI has the capability of detecting macrophages in the reticulo-endothelial system and in other sites where macrophages congregate. This is the first report where the reticuloendothelial system was specifically imaged in live animals and where driven equilibrium imaging techniques have been applied to 19F MRI.

Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system.

The potential of superparamagnetic ferrite particles as a contrast agent for magnetic resonance (MR) imaging was studied by in vitro MR spectroscopy and in vivo MR imaging in laboratory animals. After aqueous preparations of ferrite particles were administered intravenously, MR spectroscopy showed greatly decreased T2 relaxation times of liver and spleen, with only minimally altered T1, and no changes in lung, kidney, or muscle. Effects occurred within 30 minutes of injection and persisted for more than 6 months. MR imaging with pulse sequences that provide T2-dependent contrast demonstrated that ferrite produced profound signal loss from liver, spleen, and bone marrow. Sequestration of ferrite particles in hepatic reticuloendothelial cells was confirmed by means of light and electron microscopy. Because ferrite has a potent effect on MR signal and exhibits tissue-specific localization, it warrants further study as a contrast agent for MR imaging of the reticuloendothelial system (i.e., liver, spleen, and bone marrow).

Magnetic resonance imaging of fluorine in rats infused with artificial blood.

An MRI pulse sequence has been developed that enables the visualization of a perfluorocarbon (PFC) emulsion in the vascular system of rats. Images were made at 0.12T on a clinical imaging system using a small receiver coil, at intervals of approximately 2 hours, two days, two weeks, and two months after replacement of 50% of total blood volume. The most successful technique produced PA projections of the entire torso for both the fluorine and proton components. Direct comparison allowed identification of PFC in heart, lung, liver, spleen, and large vessels both in vivo and postmortem. Potential clinical applications to vascular imaging are discussed.