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Biomedical subjects

R Weissleder

Publications and source records attributed to R Weissleder.

At least 109 records · Page 6Linked to original sources
PubMed1995

MR imaging of neuronal transport in the guinea pig facial nerve: initial findings.

Certain dextran coated iron oxides such as MION (monocrystalline iron oxide nanocompound) coupled to wheat germ agglutinin (MION-WGA) have been shown to exhibit i) neuronal uptake ii) axonal transport and iii) strong magnetic effects on tissues (superparamagnetism) in which they are localized. In the current study, we utilized such an agent to visualize axonal transport in the facial nerve in vivo by magnetic resonance (MR) imaging. Following injection of the compound into the facial nerves of guinea pigs, MR images were obtained at multiple time points (1, 3 and 5 days) and the imaged tissues were processed for subsequent histological examination. In nerves that had been injected with MION-WGA, the entire nerve appeared as a uniformly hypointense structure with a calculated transport rate of 5 mm/day. By 3 days, the agent within the facial nerve was traceable by MRI from a site of injection in the buccal branch to the stylomastoid foramen. Fluorescence and autoradiography studies confirmed axonal transport. These results show that MION-based magnetopharmaceuticals can be used to demonstrate slow axonal transport, and thereby visualize functional peripheral nerves in vivo by MR imaging. The method holds promise for developmental neuroscience research as well as a method to detect neural abnormalities by MR imaging.

Animals↗
PubMed1995

Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain.

Delivery of adenovirus, herpes simplex virus (HSV), and paramagnetic monocrystalline iron oxide nanoparticles (MION) to rat brain (n = 64) was assessed after intracerebral inoculation or osmotic disruption of the blood-brain barrier (BBB). After intracerebral inoculation, the area of distribution was 7.93 +/- 0.43 mm2 (n = 9) for MION and 9.17 +/- 1.27 mm2 (n = 9) for replication-defective adenovirus. The replication-compromised HSV RH105 spread to 14.00 +/- 0.87 mm2 (n = 8), but also had a large necrotic center (3.54 +/- 0.47 mm2). No infection was detected when virus was administered intra-arterially without hyperosmotic mannitol. After osmotic BBB disruption, delivery of the viruses and MIONs was detected throughout the disrupted cerebral cortex. Positive staining was found in 4 to 845 cells/100 microns thick coronal brain section (n = 7) after adenovirus administration, and in 13 to 197 cells/section (n = 8) after HSV administration. Cells of glial morphology were more frequently stained after administration of adenovirus, whereas neuronal cells were preferentially stained after delivery of both HSV vectors and MION. In a preliminary test of vector delivery in the feline, MION was detected throughout the white matter tracts after inoculation into normal cat brain. Thus MION may be a tool for use in vivo, to monitor the delivery of virus to the central nervous system. Additionally, BBB disruption may be an effective method to globally deliver recombinant viruses to the CNS.

Adenoviridae↗
PubMed1995

[Presentation and quantification of acute myocardial infarct using antibody-bound MR contrast medium].

A magnetically labeled antimyosin (MION-AM) has previously been developed for immunospecific MR imaging in vivo. The current study was designed to extend previous feasibility studies and to correlate MR infarct size to that determined by histopathology. The left anterior coronary artery (LAD) was temporarily occluded in rabbits (n = 10) and subsequently reperfused for 1 h prior to the administration of 100 mumol Fe/kg of MION-AM (corresponding to 0.5 mg AM). One hour after i.v. administration, the infarcted myocardium appeared hypointense by MRI as a result of target-specific attachment of the magnetic T2 label to damaged but not normal myocardium. There was a close correlation between infarct size determined by MR and pathology (SE 2500/30: r = 0.92, p < or = 0.0001; SE 2500/60: r = 0.85, p < or = 0.0001). Our results are evidence that a) immunospecific magnetic probes can be utilized for cardiac MR imaging, and b) that these or similar agents may aid in the quantitation of myocardial infarct size.

Animals↗
PubMed1994

Trapping of dextran-coated colloids in liposomes by transient binding to aminophospholipid: preparation of ferrosomes.

A procedure is described that allows to increase the efficiency of the loading of liposomes with dextran-stabilized iron oxides (MION). The method produces a preparation of liposomes (REVs) with high iron oxide content as a result of transient binding of oxidized dextran with amino groups of aminophospholipids. Phosphatidylethanolamine (PE)-containing lipid mixtures (PC/DOPE/CH or SM/DOPE/CH, 9:2:9 molar ratio) in organic phase were combined with oxidized MION at pH 8. Liposomes then were obtained by reversed-phase evaporation. Liposomes, 263 +/- 89 nm in diameter, contained up to 11.8 mol Fe/mol phospholipid (encapsulation yield 49%). 10.2% of liposome-associated iron was dissociated from liposomes upon changing the pH to 4.5. When lipid compositions of extracts prepared from liposomes incubated at pH 4.5 and pH 8.0 were compared, an increase of relative PE-content in extracts of liposomes incubated at lowered pH was detected. This indicates a dissociation of imine bonds between aldehydes on the MION surface and PE. The accessibility of liposomal PE for acylation was demonstrated by modification with an activated ester of methoxy poly(ethylene glycol) succinate. Control liposomes, containing no aminophospholipid, or PE-containing liposomes obtained in the presence of non-oxidized MION, were 3.5-5-fold less effective for MION encapsulation and showed extensive aggregation.

Colloids↗
PubMed1994

MR lymphography: study of a high-efficiency lymphotrophic agent.

PURPOSE: To investigate the utility of a monocrystalline iron oxide nanoparticle (MION) as a contrast agent in magnetic resonance (MR) imaging of lymph nodes. MATERIALS AND METHODS: Pharmacokinetic data were obtained in rats after intravenous, subcutaneous, and intraarterial injection of indium-111-MION-46. MR imaging was performed to determine optimal dosages and pulse sequences in rats. Models of lymph node metastasis in rabbits and lymph node hyperplasia in rats were used to demonstrate the efficacy of MION in differentiation of malignant and benign adenopathies. RESULTS: Biokinetic data indicate that nodal accumulation occurs primarily after extravasation of agent into the interstitial space (slow component) and subsequent trapping by lymph node macrophages (fast component). Relatively low concentrations (15-25 mumol Fe per kilogram for peripheral nodes after intraarterial injection) decrease signal intensity of nodes at MR imaging. CONCLUSIONS: Lymph node accumulation of MION-46 is high. Modification of injection techniques that alter capillary permeability allows use of systemically administered agent at doses as low as 15-25 mumol Fe per kilogram.

Animals↗
PubMed1994

Determinants of in vivo MR imaging of slow axonal transport.

PURPOSE: To investigate specific surface characteristics of magnetic contrast agents based on a monocrystalline iron oxide nanoparticle (MION) that may determine their uptake and/or transport by axons. MATERIALS AND METHODS: MION were modified to have a range of surface charges or were covalently linked to wheat germ agglutinin (WGA), a neurotropic protein. Each agent was injected directly into the sciatic nerves or femoral arteries of rats (n = 22), and magnetic resonance (MR) images were obtained several days later. The imaging results then were correlated with results at postmortem histologic examination. RESULTS: Substantial uptake and/or transport by axons occurred only after intraneural injection and only if the agent had a strong surface charge or was covalently linked to WGA. The sciatic nerves appeared as uniformly hypointense structures having lengths proportional to the time from injection to imaging, and the calculated transport rates (4-7 mm/d) were consistent with slow axonal transport. Numerous Schwann cells and macrophages acquired large fractions of the injected agents and contributed substantially to the imaging results. CONCLUSION: Those characteristics of MION-based contrast agents that promote efficacy after intraneural injection may impede delivery to the nerve after intraarterial injection.

Animals↗
PubMed1994

Pancreatic receptors: initial feasibility studies with a targeted contrast agent for MR imaging.

PURPOSE: To evaluate cholecystokinin (CCK) as a target-specific vector for magnetic resonance (MR) receptor imaging of rat pancreas. MATERIALS AND METHODS: Monocrystalline iron oxide (MION) was labeled with CCK by noncovalent attachment. Receptor specificity of the conjugate was determined with competitive binding studies. Pharmacologic determinations were blood half-lives, biodistribution, time responses, dose responses, and limited toxicity. RESULTS: Specific cell binding of MION-20-CCK was saturable and inhibitable by a CCK antagonist. Blood half-life of MION-20-CCK was 20 minutes, which was shorter than that of unlabeled MION. Biodistribution studies showed a statistically significant decrease in relaxation times in pancreatic tissues from 42.7 msec +/- 2.0 to 33.8 msec +/- 1.4 (P < or = .05) but not in tumor after administration of MION-20-CCK. The half-life of MION-20-CCK in the pancreas was 3 weeks; no signs of toxicity were shown at the level tested. CONCLUSION: Target-specific MR imaging of pancreatic receptors is feasible. Additional studies are necessary to perfect binding strategies, optimize preparations, and scale up synthesis for imaging in other species.

Acute Disease↗
PubMed1994

Delivery of virus-sized iron oxide particles to rodent CNS neurons.

Delivery of viral particles to the brain is limited by the volume of distribution that can be obtained. Additionally, there is currently no way to non-invasively monitor the distribution of virus following delivery to the central nervous system (CNS). To examine the delivery of virus-sized particles across the blood-brain barrier (BBB), dextran coated, superparamagnetic monocrystalline iron oxide particles, with a hydrodynamic diameter of 20 +/- 4 nm, were delivered to rat brain by direct intracerebral inoculation or by osmotic BBB disruption with hypertonic mannitol. Delivery of these particles was documented by magnetic resonance (MR) imaging and, unexpectedly, neuronal uptake was demonstrated by histochemical staining. Electron microscopy (EM) confirmed iron particle delivery across the capillary basement membrane and localization within CNS parenchymal cells following administration with BBB disruption. This is the first histologic and ultrastructural documentation of the delivery of particles the size of virions across the blood-brain barrier. Additionally, these dextran-coated, iron oxide particles may be useful, in and of themselves, as vectors for diagnostic and/or therapeutic interventions directed at the CNS.

Animals↗
PubMed1994

Enhancement of MR angiography with iron oxide: preliminary studies in whole-blood phantom and in animals.

OBJECTIVE: We hypothesized that the previously observed T1 effect of a small monocrystalline iron oxide preparation can be exploited to decrease T1 relaxation time of blood. Such a decrease, particularly if present for a long time, could be used to improve the quality of MR angiograms. To test the hypothesis, we performed phantom studies and in vivo animal experiments. MATERIALS AND METHODS: The effect of the monocrystalline iron oxide preparation on the MR signal intensity (spoiled gradient-recalled acquisition in the steady state pulse sequences, various timing parameters) of human whole blood was first tested in a phantom (dose range of monocrystalline iron oxide preparation, 0-3 mumol Fe/ml). Subsequent experiments were performed in rats (n = 7) and in rabbits (n = 6) to determine whether predicted changes in signal intensity could be observed in vivo. RESULTS: Dose optimization studies in rats indicate that injected doses of 15-50 mumol Fe/kg (0.8-2.8 mg Fe/kg) of monocrystalline iron oxide preparation resulted in threefold to fourfold increases of aortic signal-to-noise ratio. Because of its long plasma half-life (180 min in rats), the iron oxide preparation markedly improved the quality of images of the vasculature of the lungs, abdomen, and extremities. CONCLUSION: Our experimental results suggest that this and possibly other iron oxide preparations are alternatives to compounds containing macromolecular gadolinium and could be useful for clinical MR angiography.

Animals↗
PubMed1994

Detection of pulmonary emboli by using MR angiography with MPEG-PL-GdDTPA: an experimental study in rabbits.

OBJECTIVE: A macromolecular MR contrast agent (MPEG-PL-GdDTPA), which consists of Gd-DTPA covalently attached to a polyamino acid (PL) derivatized by monomethoxy ether of polyethylene glycol (MPEG), has recently been developed. This contrast agent exhibits long intravascular retention, which makes it suitable for MR angiography. The current study was performed to test whether this agent would improve visualization of the pulmonary vasculature during MR angiography and whether it aids in the detection of pulmonary emboli in an animal model. MATERIALS AND METHODS: All experiments were performed in rabbits (n = 21), six of which were healthy and 15 of which had induced pulmonary emboli. Contrast-enhanced MR angiograms (0.02 mmol Gd/kg) were obtained at 1.5 T by using time-of-flight and phase-contrast sequences. MR images were ultimately compared with polymer casts of pulmonary arteries and/or pathologic sectioning. RESULTS: MR angiograms obtained before the administration of a contrast agent were of low quality primarily because of low vessel/background signal-to-noise ratio, presumably due to slow and complex flow in the pulmonary vasculature. After IV administration of the contrast agent, pulmonary arteries could be visualized up to the third-order branches. Of the 18 pathologically or angiographically proved emboli, 16 could be detected with contrast-enhanced MR angiography. CONCLUSION: Our results indicate that macromolecular contrast agents with long blood half-lives, such as MPEG-PL-GdDTPA, increase signal intensity of pulmonary vessels, improve the quality of MR angiography, and increase the detectability of pulmonary emboli.

Animals↗
PubMed1994

T2-weighted MR imaging of the upper part of the abdomen: should fat suppression be used routinely?

OBJECTIVE: Fat suppression has shown promise in improving the quality of T2-weighted spin-echo MR images of the upper part of the abdomen. The purpose of this study was to determine whether fat-suppressed images should be routinely used in lieu of conventional images. Accordingly, we prospectively compared the two techniques in a series of patients with both normal and abnormal findings in the upper part of the abdomen. MATERIALS AND METHODS: Conventional and fat-suppressed T2-weighted spin-echo images (3000/80,160 [TR/TE]) were obtained in 45 consecutive patients referred for MR imaging of the upper part of the abdomen. Thirty-three patients had abnormal findings, and 22 of those 33 patients had histologic or follow-up confirmation of the diagnosis (14 with metastasis, one with hepatoma, four with hemangiomas, and three with cysts). Signal intensities (hepatic lesions, liver, spleen) and noise were measured to calculate signal-to-noise ratios and contrast-to-noise ratios. Qualitative comparison (liver, hepatic lesions, porta hepatis, spleen, pancreas, bowel, kidneys, adrenal glands, noise), evaluation of the number of hepatic lesions, and characterization of hepatic lesions were done by independent observers. RESULTS: Compared with conventional images, fat-suppressed images had higher signal-to-noise ratios (lesions, liver, spleen) and contrast-to-noise ratios (lesion-liver and spleen-liver) (p < .005). In qualitative comparison, three of three radiologists preferred fat-suppressed over conventional images for depiction of hepatic lesions and all upper abdominal organs except the liver, for which no clear preference was shown for either technique. Detection rates for hepatic lesions were similar with both types of images (observer 1: 112 lesions on fat-suppressed vs 118 on conventional images, observer 2: 142 vs 135), as was the characterization of hepatic lesions (91% accuracy on fat-suppressed images and 84% accuracy on conventional images, for 22 proved lesions and two observers). CONCLUSION: Fat-suppressed T2-weighted spin-echo MR images were better than non-fat-suppressed images for evaluation of the upper part of the abdomen. These results suggest that fat suppression should be routinely used in T2-weighted MR imaging of the upper part of the abdomen.

Abdomen↗
PubMed1994

Synthetic copolymer kit for radionuclide blood-pool imaging.

UNLABELLED: A synthetic blood pool imaging agent labeled with 99mTc is reported. METHODS: The agent, methoxypolyethylene glycol-poly-L-lysyl-diethylenetriaminepentaacetate monoamide was synthesized from a covalent graft copolymer of methoxypolyethylene glycol succinate (molecular weight 5.1 kD) and poly-L-lysine (molecular weight average 35.6 kD) with subsequent modification of the product with diethylenetriamineacetyl residues. The polymer was formulated into a kit that contained Sn(II) and sodium acetate for radiolabeling with 99mTc. Biodistribution studies were performed in rats. Blood-pool imaging and blood clearance determination was carried out in rabbits and in a rhesus monkey. RESULTS: The 99mTc-labeled agent [specific activity greater than 3.7 GBq/mg; radiochemical purity more than 98% by thin-layer and high-performance liquid chromatography (HPLC)] demonstrated remarkable stability in solution (pH 5.5-6.5) with no radioactive products of degradation detectable by HPLC even at 24 hr postlabeling. The agent exhibited prolonged circulation in the blood with a half-life of 31.5 hr in rabbits. Biodistribution in rats showed a lack of substantial accumulation of the agent in the reticuloendothelial system. Sequential acquisitions were performed in a rhesus monkey. The 99mTc-labeled polymer kit was compared with the 99mTc-red blood cells (RBCs) labeled in vitro. Both methods produced similar heart-to-lung ratios. The ratios remained essentially unchanged for up to 15 hr postinjection. CONCLUSION: The 99mTc-labeled methoxypolyethylene glycol-poly-L-lysyl-diethylenetriamine pentaacetate monoamide is an attractive alternative to radiolabeled RBCs for blood pool imaging applications.

Animals↗
PubMed1993

Monocrystalline iron oxide nanocompounds (MION): physicochemical properties.

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.

Ferric Compounds↗
PubMed1993

MR imaging of slow axonal transport in vivo.

Three magnetopharmaceuticals based on a monocrystalline iron oxide nanocompound (MION) are evaluated as potential contrast agents for demonstrating axonal transport in vivo by magnetic resonance (MR) imaging. One agent has a strong positive charge, one has a strong negative charge, and the third is covalently linked to wheat germ agglutinin, a plant lectin with a high affinity for axon terminals. All three agents were tagged with rhodamine, and fluorescence microscopy was used to determine their fate after administration and to validate the imaging results. Following injection into or near various neural structures in the motor and visual systems of rats, MR images were obtained at multiple times up to 11 days later, and the imaged tissues were processed for subsequent histological examination. Similar results were obtained with all three agents. Axonal transport was not seen by MR imaging or fluorescence microscopy when the agents were injected into the calf muscles, the vitreous of the eye, or the superior colliculus. However, bidirectional axonal transport was shown unequivocally by both methods after injection directly into the site of a focal crush injury to the sciatic nerve. The nerve, which otherwise is isointense with surrounding tissues on MR images, appeared as a uniformly hypointense structure having a length approximately in proportion to the time from injection to imaging. By 11 days, the course of the nerve was traceable from its component roots in the cauda equina to its bifurcation into the tibial and common peroneal nerves in the leg. A transport rate of about 5 mm/day was calculated, which is consistent with the mechanism of slow transport. MION-based magnetopharmaceuticals thus can be used to demonstrate slow axonal transport, and thereby visualize peripheral nerves, in vivo by MR imaging.

Animals↗
PubMed1993

MION-ASF: biokinetics of an MR receptor agent.

Receptor-directed MR contrast agents are currently being designed to improve sensitivity and specificity of MR imaging and to provide for functional MR imaging. In the current study we have synthesized a conjugate of asialofetuin (ASF), a bovine plasma protein with a known, high affinity for the hepatic asialoglycoprotein receptor, and a well defined, single crystal superparamagnetic label (monocrystalline iron oxide nanoparticle, MION). MION-ASF is cleared from the circulation more than 300 times faster than MION, has a 3.7 times higher hepatic accumulation, increases liver R2 relaxivity 2.8-fold compared to MION, and accumulates in hepatocytes unlike MION, which accumulates only in macrophages. Competition assays indicate that receptor-mediated hepatocyte uptake can be competitively blocked and that this effect can be demonstrated by imaging. These studies indicate that sensitive iron oxide based probes can be developed for functional MR imaging.

Animals↗
PubMed1993

AUR Memorial Award 1993. A drug system (PDH) for interventional radiology. Synthesis, properties, and efficacy.

RATIONALE AND OBJECTIVES: The authors synthesized and tested a novel hydrogel system proposed for use in extra- and intravascular radiologic interventions, such as chemoembolizations and embolizations, and as a vehicle for sustained drug release. MATERIALS: The material was specifically designed to meet the prerequisites of biodegradation, biocompatibility, low immunogenicity, low toxicity, and easy use. The material consists of a protein backbone cross-linked with activated bifunctional polyethyleneglycol (PEG) derivatives (PEG-derivatized hydrogel, [PDH]) to which are attached therapeutic (e.g., doxorubicin, a chemotherapeutic agent = PDH-dx) or diagnostic labels (e.g. Gd-DTPA). RESULTS: PDH-dx effectively reduced the risk of local tumor recurrence in a rat model when implanted locally after surgical tumor removal. After administration, PDH is degraded by proteases release from macrophages; implantations of 1 mL samples into paraspinal muscles of rats were completely absorbed within 4 weeks and its constituents were metabolized. Antibody titers (total Ig response) against the PDH were not detectable 1 week after implantation, whereas protein control substances elicited a strong response. CONCLUSIONS: PDH and its derivatives are relatively nontoxic, biodegradable materials for use in radiologic interventions and as a vehicle for sustained drug release.

Animals↗
PubMed1993

A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies.

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.

Animals↗