Molecular and cellular MR imaging is a rapidly growing field that aims to visualize targeted macromolecules or cells in living organisms. In order to provide a different signal intensity of the target, gadolinium-based MR contrast agents can be employed although they suffer from an inherent high threshold of detectability. Superparamagnetic iron oxide (SPIO) particles can be detected at micromolar concentrations of iron, and offer sufficient sensitivity for T2(*)-weighted imaging. Over the past two decades, biocompatible particles have been linked to specific ligands for molecular imaging. However, due to their relatively large size and clearance by the reticuloendothelial system (RES), widespread biomedical molecular applications have yet to be implemented and few studies have been reproduced between different laboratories. SPIO-based cellular imaging, on the other hand, has now become an established technique to label and detect the cells of interest. Imaging of macrophage activity was the initial and still is the most significant application, in particular for tumor staging of the liver and lymph nodes, with several products either approved or in clinical trials. The ability to now also label non-phagocytic cells in culture using derivatized particles, followed by transplantation or transfusion in living organisms, has led to an active research interest to monitor the cellular biodistribution in vivo including cell migration and trafficking. While most of these studies to date have been mere of the ‘proof-of-principle’ type, further exploitation of this technique will be aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors. Copyright © 2004 John Wiley & Sons, Ltd.

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/pdf/10.1002/nbm.924

Iron oxide MR contrast agents for molecular and cellular imaging.

Recent advances in iron oxide nanocrystal technology for medical imaging

The pharmacokinetics (distribution, metabolism, bioavailability, excretion) and toxicity (acute and subacute toxicity, mutagenicity) of a superparamagnetic iron oxide preparation (AMI-25), currently used in clinical trials, were evaluated by 59Fe radiotracer studies, measurements of relaxation times, the ability to reverse iron deficiency anemia, histologic examination, and laboratory parameters. One hour after administration of AMI-25 to rats (18 mumol Fe/kg; 1 mg Fe/kg), 82.6 +/- 0.3% of the administered dose was sequestered in the liver and 6.2 +/- 7.6% in the spleen. Peak concentrations of 59Fe were found in liver after 2 hr and in the spleen after 4 hr. 59Fe slowly cleared from liver (half-life, 3 days) and spleen (half-life, 4 days) and was incorporated into hemoglobin of erythrocytes in a time-dependent fashion. The half-time of the T2 effect on liver and spleen (24-48 hr) was shorter than the 59Fe clearance, indicating metabolism of AMI-25 into other forms of iron. IV administration of AMI-25 (30 mg Fe/kg) corrected iron-deficiency anemia and showed bioavailability similar to that of commercially available IV iron preparations within 7 days. No acute or subacute toxic effects were detected by histologic or serologic studies in rats or beagle dogs who received a total of 3000 mumol Fe/kg, 150 times the dose proposed for MR imaging of the liver. Our results indicate that AMI-25 is a fully biocompatible potential contrast agent for MR.

https://www.ajronline.org/doi/pdfplus/10.2214/ajr.152.1.167

Superparamagnetic iron oxide: Pharmacokinetics and toxicity

We have developed a novel water-dispersible oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticle formulation that can be loaded easily with high doses of water-insoluble anticancer agents Drug partitions into the OA shell surrounding iron oxide nanoparticles, and the Pluronic that anchors at the OA−water interface confers aqueous dispersity to the formulation Neither the formulation components nor the drug loading affected the magnetic properties of the core iron oxide nanoparticles Sustained release of the incorporated drug is observed over 2 weeks under in vitro conditions The nanoparticles further demonstrated sustained intracellular drug retention relative to drug in solution and a dose-dependent antiproliferative effect in breast and prostate cancer cell lines This nanoparticle formulation can be used as a universal drug carrier system for systemic administration of water-insoluble drugs while simultaneously allowing magnetic targeting and/or imaging Keywords: Sustained release; wat

/pdf/iron-oxide-nanoparticles-for-sustained-delivery-of-12swyzskz8.pdf

Iron oxide nanoparticles for sustained delivery of anticancer agents.

Although experimental and pathological studies suggest an important role for ischemia in the majority of fatal cases of traumatic brain injury, ischemia has been a rare finding in most clinical studies of cerebral blood flow (CBF) in head-injured patients. The hypothesis of the present study was that cerebral ischemia occurs in the first few hours after injury, but that CBF measurements have not been performed early enough. Early measurements of CBF (by the 133Xe intravenous method) and arteriovenous oxygen difference (AVDO2) were obtained in 186 adult head-injured patients with a Glasgow Coma Scale score of 8 or less, and were correlated with neurological status and outcome. During the first 6 hours after injury, CBF was low (22.5 +/- 5.2 ml/100 gm/min) but increased significantly during the first 24 hours. The AVDO2 followed the opposite course; the decline of AVDO2 was most profound in patients with low motor scores, suggesting relative hyperemia after 24 hours. A significant correlation between motor score and CBF was found in the first 8 hours after injury (Spearman coefficient = 0.69, p less than 0.001), but as early as 12 hours postinjury this correlation was lost. A similar pattern was found for the relationship between CBF and outcome. Cerebral blood flow below the threshold for infarction (CBF less than or equal to 18 ml/100 gm/min) was found in one-third of the studies obtained within 6 hours, the incidence rapidly decreasing thereafter. A low CBF after 24 hours was not generally associated with a high AVDO2, and was probably a reflection of low oxidative metabolism rather than frank ischemia. In 24 patients, a CBF of 18 ml/100 gm/min or less was found at some point after injury; the mortality rate was significantly higher in this subgroup, and survivors did worse. In some cases, ischemia was successfully treated by reducing hyperventilation or inducing arterial hypertension. These results support the above hypothesis, and suggest that early ischemia after traumatic brain injury may be an important factor determining neurological outcome. Moreover, these data indicate that early hyperventilation or lowering of blood pressure to prevent brain edema may be harmful.

Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia.

Neuroblastoma is a unique tumor of childhood that has a wide range of malignant expression. The prognoses range from excellent, with minimal treatment required, for patients with localized tumors o...

31P Nuclear magnetic resonance spectroscopic investigation of human neuroblastoma in situ

Most contrast agents used in NMR imaging studies to date have been paramagnetic. However, it is also possible to obtain selective contrast with a ferromagnetic agent, and these agents are potentially more sensitive than paramagnetic compounds because of their large magnetic moments. The water relaxation ability of ferromagnetic, albumin-coated magnetite (Fe3O4) particles has been investigated. These particles are quite effective at reducing both T1 and T2 at relatively low particle concentrations. The potential applications of these particles include improved visualization of the liver, gastrointestinal tract, and genitourinary tract, as well as specific targeting and detection of small tumors or other cells with unique surface receptors. © 1986 Academic Press, Inc.

Ferromagnetic contrast agents: a new approach.

Relaxation times in systems with chemical exchange: Approximate solutions for the nondilute case

Specificity of creatine kinase for guanidino substrates. Kinetic and proton nuclear magnetic relaxation rate studies.

The objective of this study was to evaluate simultaneous 31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (PaO2 20 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO2 20 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 mumol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metabolic acidosis on the creatine kinase equilibrium and not to a delayed recovery of the ATP/ADP ratio. Third, the observed rate of lactate clearance from the cell is zero-order (k = 0.36 mumol/g/min) for lactate levels greater than 5 microns/g and may be composed of both lactate efflux from the cell and lactate oxidation.

Alan C. McLaughlin

Papers

31P Nuclear magnetic resonance spectroscopic investigation of human neuroblastoma in situ

Ferromagnetic contrast agents: a new approach.

Relaxation times in systems with chemical exchange: Approximate solutions for the nondilute case

Specificity of creatine kinase for guanidino substrates. Kinetic and proton nuclear magnetic relaxation rate studies.

Simultaneous 31P- and 1H-nuclear magnetic resonance studies of hypoxia and ischemia in the cat brain.