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Biomedical subjects

R Weissleder

Publications and source records attributed to R Weissleder.

At least 91 records · Page 5Linked to original sources
PubMed1997

A long-circulating co-polymer in "passive targeting" to solid tumors.

A co-polymer of O-methyl polyethylene(glycol)-O'-succinate (MPEGs, m.w. 5100) and poly-l-lysine (PL, median m.w. 32700, degree of polymerization 256) has been synthesized by covalent grafting. The resultant MPEGs-PL (30% modification degree of epsilon-amino groups) had a hydrodynamic diameter corresponding to a 690 kD protein. Free amino groups (180/mol of the co-polymer) were used for conjugation of diethylene pentaacetic or succinic acid residues to MPEGs-PL. The potential of the resultant compound as a carrier of therapeutic and diagnostic drugs was studied using a rodent carcinoma models. The co-polymer had a blood pool half-life of 36h in adenocarcinoma-bearing rats. Radioactively labeled preparations were resistant to trans-chelation with apotransferrin and stable in blood for 24 h. The co-polymer accumulated in solid tumors at the level of 1.5-2% injected dose/g of tumor in 24 h. At that time, 34-40% of the accumulated polymer was associated with tumor cell fraction. The co-polymer non-covalently associated with cis-diamminedichloroplatinum(II), showed a cytostatic effect against mouse F9 carcinoma, and induced a reversal in tumor growth after intravenous administration.

Animals↗
PubMed1996

[Development and experimental use of receptor-specific MR contrast media].

The authors describe the feasibility of developing receptor-specific MR contrast agents for the improved detection of pathology and assessment of organ function. Receptor specificity of MR contrast agents can be achieved by binding of receptor-specific carriers to ligands. This concept leads towards a decrease in dose and thus in toxicity. Specific attachment to parenchymal cells improves tumor-organ contrast and therefore tumor detection. Specific uptake mechanisms also enable the assessment of organ function. Future design concepts of novel MR contrast agents may consider the desired uptake in specific cells or organs (ovaries, adrenal glands, lymph nodes etc.) with subsequent synthesis of appropriate carriers.

Animals↗
PubMed1996

Macromolecular intravenous contrast agent for MR lymphography: characterization and efficacy studies.

PURPOSE: To determine the pharmacokinetic and magnetic resonance (MR) imaging properties of diethylenetriaminepentaacetic acid (DTPA) conjugated with a polyglucose-associated macrocomplex (PGM), which accumulates in lymph nodes. MATERIALS AND METHODS: In 124 normal and 20 tumor-bearing rats, Gd-DTPA PGM was administered intravenously in doses of 2, 10, 20 mumol gadolinium per kilogram of tissue. RESULTS: Mean blood half-life was 2 hours. Maximum accumulation in peripheral (33.0% injected dose [ID]/g +/- 16.2 [standard deviation]) and central lymph nodes (63.2% ID/g +/- 16.5) was observed within 24 hours after administration. The optimum dose range was 10-20 mumol Gd/kg in rats. At 24 hours after administration of 20 mumol Gd/kg, the signal-to-noise ratio increased from 30.9 +/- 0.4 to 83.2 +/- 5.2 in normal lymph nodes (P < .001). Differentiation between normal and metastatic lymph nodes was improved. CONCLUSION: When labeled with Gd-DTPA, the PGM-based graft copolymer significantly increases signal intensity at MR imaging of normal but not metastatic lymph nodes without causing distortion artifacts.

Animals↗
PubMed1996

Targeted contrast agents in MR imaging.

The use of target specific MR contrast agents can dramatically improve information obtained by MR imaging. This review outlines the various components of target specific MR contrast agents, including various carriers (e.g., monoclonal antibodies, peptides, proteins, polysaccharides, polymers, liposomes, and cells) as well as magnetic labels (e.g., metal ion chelates, free radicals, and iron oxides) and focusses on some promising clinical applications.

Antibodies, Monoclonal↗
PubMed1996

Liver. II: Iron oxide-based reticuloendothelial contrast agents for MR imaging. Clinical review.

Iron oxide-based compounds are a new class of MR contrast agents that have a wide range of clinical applications. The biodistribution and subsequent influence on the MR image depends on the particle size. Iron oxides can be used to increase contrast-to-noise ratio, facilitating the visibility of focal liver lesions. Other applications include blood-pool imaging and targeting the reticuloendothelial system and cell surface receptors.

Contrast Media↗
PubMed1996

[Lymph node diagnosis with imaging methods. An overview with special reference to recent developments in the area of MR contrast media].

The main problem in current lymph node imaging is the lack of reliable criteria for differential diagnosis between benign and malignant nodes, the main criterion being size. To reliably opacify all lymph nodes in the body, an intravenous contrast agent is therefore necessary. Two new contrast agents for MRI seem promising: lymphotropic iron oxides and Gadolinium DTPA-PGM. After intravenous administration these agents accumulate in phagocytic cells of normal lymph nodes but are excluded from nodes in which phagocytic activity is replaced. While iron oxides are already in clinical studies, GD-DTPA-PGM is in preclinical studies. Both agents seem to significantly improve the differential diagnosis between benign and malignant lymph nodes irrespective of size.

Contrast Media↗
PubMed1996

Drug delivery to lymphatic tissue.

Efficient diagnosis and therapy of diseases affecting lymph nodes rely on the availability of drugs that are retained by lymph nodes. Intralymphatically or interstitially administered macromolecular carriers accumulate efficiently in draining lymph nodes. However, because of the high variability of lymphatic networks and drainage routes, systemic administration of lymphotropic carriers would be preferable and currently represents a major focus in lymphotropic drug design. This review focuses on advances in the development of intravenous drug carriers and briefly discusses agents used for local delivery.

Administration, Oral↗
PubMed1996

MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis.

PURPOSE: To determine if tumor-specific monoclonal antibodies conjugated to superparamagnetic monocrystalline iron oxide nanoparticles can be used to yield specific diagnoses with the use of MR imaging. METHODS: Monoclonal antibodies conjugated to monocrystalline iron oxide nanoparticles were given to nude rats with intracranial tumors either by intravenous injection, intraarterial injection with osmotic blood-brain barrier disruption, or direct intratumoral inoculation. Either L6, a tumor-specific antibody, or P-1.17, a control isotype-matched antibody, was used. Coronal T1-weighted, T2-weighted, and spoiled gradient-recalled acquisition in the steady state images were obtained before, 30 minutes after, 6 hours after, and 24 hours after injection. RESULTS: Intravenous injection of greater than 2 mg of the tumor-specific antibody showed a specific pattern of enhancement of the tumors with the largest concentration of antibody in the area with the greatest density of tumor cells. The control antibody showed nonspecific changes. After intraarterial injection with barrier disruption to increase delivery globally or direct inoculation to increase delivery focally, no specific enhancement pattern was seen. CONCLUSION: Monoclonal antibodies conjugated with monocrystalline iron oxide particles may provide a method to obtain specific diagnoses with the use of MR imaging.

Animals↗
PubMed1995

MR lymphography with a lymphotropic T1-type MR contrast agent: Gd-DTPA-PGM.

A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T1-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection. Maximum concentrations of Gd-DTPA-PGM were found in popliteal and paraaortic lymph nodes within 24 h after SC administration, and highest lymph node SNR values were obtained by MR imaging at this time point. The optimum imaging dose was 6-12 mumol Gd/kg. Tumor-lymph node contrast increased from 0.0 +/- 1.2 precontrast to 19.2 +/- 6.5 (spoiled gradient echo sequence, TR 50/TE 7/flip angle 60 degrees) postcontrast and conspicuity of nodal metastases was improved. Gd-DTPA-PGM accumulates in lymph nodes after SC administration and significantly enhances lymph node signal intensity of normal animals but not metastatic lymph nodes.

Animals↗
PubMed1995

An organotypical in vitro model of the liver parenchyma for uptake studies of diagnostic MR receptor agents.

Testing of receptor-specific MR contrast agents targeted to the liver is hampered by a shortage of viable in vitro models with in vivo-like hepatocellular morphology. Coated pits are ultrastructural signs of an active receptor mediated endocytosis in hepatocytes. Expression of coated pits by matrix overlaid hepatocytes was studied by transmission electron microscopy. Binding of a rhodaminated asialoglycoprotein receptor agent (MION-ASF-rh) was assessed by fluorescence microscopy. Fluorescence of cells exposed to MION-ASF-rh with D(+)-galactose reduced fluorescent light emission to a level of 58% of MION-ASF-rh-induced fluorescence. After preincubation with the hepatotoxin CCl4 a dose-dependent decrease in fluorescent light emission resulted. Hepatocytes maintained a homogeneous cell surface expression, with microprojections, coated pits, and vesicles on both sinusoidal surfaces. Matrix overlaid primary hepatocytes constitute a viable, morphologically and functionally differentiated model. This model can be used to study receptor binding, uptake, and blockage of diagnostic magnetopharmaceuticals under controlled conditions.

Animals↗
PubMed1995

Selective uptake of viral and monocrystalline particles delivered intra-arterially to experimental brain neoplasms.

In this study we investigated the intra-arterial delivery of viral and nonviral particles to experimental brain tumors. A herpes simplex virus (HSV) vector and monocrystalline iron oxide nanoparticles (MION) were injected into the internal carotid artery of Fisher 344 rats harboring intracerebral 9L gliosarcomas, using bradykinin to disrupt the blood-tumor barrier. Brain and internal organs were stained both for virus-mediated gene expression and for iron. Quantitative comparisons of gene expression and MION uptake with and without blood-tumor barrier disruption were performed in the center and at the periphery of the tumor mass, as well as in normal brain. In addition, MION distribution was traced in vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cells was greatly enhanced by intra-carotid bradykinin infusion. Virus-mediated expression of the HSV-thymidine kinase (TK) and beta-galactosidase gene products was highest at the tumor periphery as compared to the tumor center. Selective HSV infection of multiple tumor foci was achieved in both hemispheres without affecting normal brain. MION uptake was high at the tumor periphery even without blood-tumor barrier disruption. Bradykinin increased MION uptake predominantly in the center of the tumor with virtually no effect at the periphery. These findings show that selective blood-tumor barrier disruption by bradykinin can be used to enhance HSV-mediated gene delivery to tumor cells in the periphery of brain tumors. A crucial aspect in the treatment of malignant brain tumors is the eradication of tumor cells infiltrating the brain; bradykinin may facilitate access of vectors to these areas by selective disruption of their neovasculature.

Animals↗
PubMed1995

Cellular uptake and trafficking of a prototypical magnetic iron oxide label in vitro.

RATIONALE AND OBJECTIVES: Target-specific magnetic resonance (MR) contrast agents are being developed to improve the accuracy of MR imaging. The purpose of this study was to determine the mechanism of cell uptake, and modes of intracellular trafficking of a prototypical iron oxide label (RMA) used in the synthesis of some target-specific MR contrast agents. METHODS: The prototypical agent (RMA) consisted of a dextran-coated monocrystalline iron oxide that was modified with rhodamine (fluorescent label) and opsonized with albumin. Fluorescence microscopy was performed in a phagocytic C6 cell line and in murine bone marrow macrophages. Immunohistochemistry against lysosomal markers was used to confirm the intracellular location of the label. RESULTS: RMA was identified inside cells after incubation at concentrations as low as 4.0 x 10(-10) M Fe, typically observed with receptor mediated endocytosis and several orders of magnitude lower than that expected with fluid phase pinocytosis. Cell uptake could be inhibited by excess protein but not by dextran. RMA localized initially to tubular and to round intracellular organelles and co-localized with an antibody against a murine lysosomal glycoprotein antibodies (LGP-A) in macrophages. Three days after incubation, RMA was concentrated in perinuclear vesicles, which most likely represent terminal lysosomes where final breakdown appears to occur. CONCLUSIONS: The mechanism of cellular uptake of a prototypical opsonized iron oxide label is consistent with receptor-mediated endocytosis. Immediately after cell contact, RMA localizes to the lysosomal compartment and at long time points reside in vesicles that by morphology and distribution appear to be terminal lysosomes. Iron oxides therefore demonstrate metabolism via the lysosomal pathway.

Albumins↗
PubMed1995

Quantitation of slow drug release from an implantable and degradable gentamicin conjugate by in vivo magnetic resonance imaging.

A biodegradable model hydrogel containing a covalently bound aminoglycoside in which drug release can be monitored by magnetic resonance imaging (MRI) in vivo was developed. The hydrogel consists of the bishydroxysuccinimide ester of polyethylene glycol disuccinate cross-linked albumin, to which gentamicin and Gd-diethylenetriaminepentaacetic acid are covalently attached in stochiometric quantities. MRI allowed us to depict the three-dimensional structure of implanted gels, to accurately calculate their volumes, and thus to calculate the concentration of hydrogel-bound gentamicin. The correlation coefficient for the concentration of released gentamicin and the hydrogel volume was 0.965. Free and hydrogel-released gentamicin conjugates had similar antibiotic efficacies when tested in microbiological agar diffusion assays. In vivo, hydrogel-released gentamicin had a longer half-life in plasma than unaltered gentamicin (5.6 versus 0.7 h), presumably because of residual bound polyethylene glycol residues. Hydrogel implants into rats resulted in a prolonged (7 to 10 days) release of gentamicin and a decreased 24-h mortality in mice infected with a lethal dose of Pseudomonas aeruginosa. The results indicate the feasibility of imaging and quantitating therapeutic drug concentrations in vivo by MRI.

Animals↗
PubMed1995

Experimental gastrointestinal hemorrhage: detection with contrast-enhanced MR imaging and scintigraphy.

PURPOSE: To examine the use of O-methoxy poly(ethylene)glycol-O'-succinyl-N-epsilon-poly(L-lysyl) gadolinium diethylenetriaminepentaacetic acid (MPEG-PL-Gd-DTPA) as a potential magnetic resonance (MR) angiographic contrast agent for the detection of gastrointestinal (GI) bleeding. MATERIALS AND METHODS: MPEG-PL-Gd-DTPA was used for blood pool enhancement, and MPEG-PL-technetium-99m DTPA was used for planar nuclear imaging studies. GI bleeding was tested in rats by controlled injection of contrast material-doped blood through a jejunostomy catheter. MR imaging was performed at 1.5 T. RESULTS: Ideal flip angle, used with a spoiled gradient-echo pulse sequence, was 40 degrees. The smallest amount of hemorrhage detected at MR imaging was 0.05 mL; at nuclear imaging it was 0.02 mL. With the superior spatial resolution of MR imaging, individual loops of contrast material-filled bowel were identified and bleeding points were pinpointed. CONCLUSION: GI hemorrhage can be easily detected at MR imaging if a long circulating macromolecular contrast agent is used to decrease the T1 of extravasated blood.

Animals↗
PubMed1995

Cerebral iron oxide distribution: in vivo mapping with MR imaging.

PURPOSE: To map the distribution of an iron oxide label in the central nervous system with in vivo magnetic resonance (MR) imaging. MATERIALS AND METHODS: Unilateral osmotic disruption of the blood-brain barrier (BBB) in rats (n = 40) was followed by injection of monocrystalline iron oxide nanoparticles (MION) into the carotid artery. MR images (1.5 T) were obtained in and ex vivo, and results were correlated with histologic section-matched iron maps. RESULTS: A mean of 0.2% of the injected MION was found in the brain 24 hours after unilateral osmotic disruption of the BBB. The spatial distribution of iron oxide within the brain correlated with areas known to have high relative perfusion. Iron was found in cell bodies and dendrites of cortical neurons and astrocytes and in the interstitial space. The threshold in concentration for detection of MION in the brain was 62.2 ng Fe/mm2. CONCLUSION: MR imaging is well suited to noninvasive in vivo mapping of the intracerebral iron oxide distribution.

Animals↗
PubMed1995

MR imaging of phagocytosis in experimental gliomas.

PURPOSE: To determine whether phagocytosis can be observed in vivo in glioma cells. MATERIALS AND METHODS: Rat C6 glioma cells were studied in culture and after intracerebral implantation into 13 rats. Monocrystalline iron oxide nanoparticles (MION), a model marker of phagocytosis, was administered intravenously to tumor-bearing rats at 2-20 mg of iron per kilogram. Magnetic resonance (MR) imaging was performed at multiple time points. RESULTS: Glioma cells in culture showed uptake of MION in amounts of up to 10 ng of iron per 10(6) cells, corresponding to approximately 50,000 particles per cell. Fluorescently labeled MION was found to be located primarily in tubular lysosomes. Intracerebral gliomas showed characteristic changes in signal intensity at MR imaging that peaked 12 hours after administration of MION and lasted up to 5 days; these changes corresponded to uptake and subsequent biodegradation of MION by tumor cells. CONCLUSION: Phagocytosis of glioma cells can be detected in vivo with iron oxide-enhanced MR imaging, and this may permit accurate delineation of tumor margins.

Animals↗
PubMed1995

Inflammation: imaging with methoxy poly(ethylene glycol)-poly-L-lysine-DTPA, a long-circulating graft copolymer.

PURPOSE: To test whether a nontargeted, long-circulating, synthetic polymer accumulates in areas of inflammation, with high capillary permeability and increased regional blood flow. MATERIALS AND METHODS: Methoxy poly(ethylene glycol)-poly-L-lysine (PL)-diethylenetriaminepentaacetic acid (MPEG-PL-DTPA) was labeled with technetium-99m for scintigraphy and with gadolinium for magnetic resonance (MR) imaging. Eleven Escherichia coli-infected rats were injected with 1.0 mCi (37 MBq) of Tc-99m-labeled MPEG-PL-DTPA for scintigraphy. Twelve rats underwent 1.5-T MR imaging after intravenous injection of gadolinium-labeled MPEG-PL-DTPA (35 mumol/kg). RESULTS: Tc-99m-labeled MPEG-PL-DTPA demonstrated nearly eight-fold higher accumulation in infected muscle when compared with normal muscle. Scintigrams and MR images showed areas of inflammation with peak accumulation at 24 hours after injection of Tc-99m- or gadolinium-labeled MPEG-PL-DTPA. CONCLUSION: Nontargeted, long-circulating, copolymers can efficiently accumulate in sites of inflammation and thus represent an alternative to inflammation-specific agents.

Animals↗