We have previously described a novel monocrystalline iron oxide nanocompound (MION), a stable colloid that enables target specific MR imaging. In this study, the physicochemical properties of MION are reported using a variety of analytical techniques. High resolution electron microscopy indicates that a MION consists of hexagonal shaped electron-dense cores of 4.6 +/- 1.2 nm in diameter. This iron oxide core has an inverse spinel crystal structure which was confirmed by x-ray powder diffraction. Chemical analysis showed that each core has 25 +/- 6 dextran molecules (10 kD) attached, resulting in a unimodal hydrodynamic radius of 20 nm by laser light scattering. Because of the flexibility of the dextran layer, the radius is only 8 nm in nonaqueous reverse micelles. At room temperature, MION exhibit superparamagnetic behavior with an induced magnetization of 68 emu/g Fe at 1.5 T. Mössbauer studies show that the saturation internal magnetic field is 505 KOe, and blocking temperature is at 100 K. The R1 relaxivity of MION is 16.5 (mM.sec)-1 and the R2 relaxivity is 34.8 (mM.sec)-1 in aqueous solution at 37 degrees C and 0.47 T. In vitro phantom studies show that the detectability of MION in liver tissue is less than 50 nmol Fe/g tissue using gradient echo imaging techniques.
The authors developed and evaluated a polymer as a contrast agent for magnetic resonance (MR) angiography. The agent consists of a monomethoxy ether of poly(ethylene glycol) covalently attached to poly(L-lysine) (PL), with PL serving as the carrier of gadolinium diethylenetriaminepentaacetic acid (DTPA). Immunogenicity and toxicity studies were performed in mice, and biokinetic and metabolic studies were performed in rats. Dose response studies were performed with a three-dimensional time-of-flight sequence in eight rats. No permanent immune response was elicited against Gd-DTPA or the carrier molecule, and accumulation in organs of the reiculoendothelial system was minimal. The blood half-life of the agent was 14 hours. A dose of 20 mumol of gadolinium per kilogram of body weight was sufficient to increase the vessel-muscle ratio by four- to fivefold. Contrast was substantially improved and remained unchanged 2 hours after contrast medium administration, and good visualization of four orders of vasculature was allowed.
A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.
Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebro-spinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active “pumping” of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.
29Si nuclear magnetic resonance (NMR) spectroscopy is applied to study the degradation of polysiloxanes (silicones) in vivo. Our results with animal models show that silicone migrates from the implant to the liver (29Si resonance at -20 ppm) and new silicon containing compounds form after the silicones are introduced into the rats. The new 29Si resonances in the chemical shift range of -40 to -85 ppm are related to hydrolyzed silicone, those at -90 to -115 ppm are indicative of the presence of silica (SiO2), and the peaks observed at -120 to -150 are related to high coordinated silicon complexes. These resonances are not present in the 29Si spectra of the silicones before implantation. Our findings demonstrate that silicones are not metabolically inert.
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