Biomedical subjects

W Maier-Borst

Publications and source records attributed to W Maier-Borst.

At least 19 recordsLinked to original sources

PubMed1995

The injection of heparin prolongs the plasma clearance of oxidized low density lipoprotein in the rat.

There is evidence that oxidized-LDL plays an important role in atherogenesis. We now report on the in vivo interaction between unfractionated heparin and oxidized LDL in rats. The recovery rates of the native LDL particles ranged between 75% and 85% of the injected dose. Heparin did not interfere with the clearance rates of native LDL. After administration of radioactive labeled oxidized-LDL particles, 26% of the material was measured in circulation after 5 minutes, 8% after 20 minutes, and 3% after 60 minutes. After injection of heparin 2 minutes prior to oxidized-LDL tracer particles, 44% of the tracer was found in blood after 5 minutes, 23% after 20 minutes, and 9% after 60 minutes. Oxidized-LDL tracer particles disappeared from blood with an alpha half-life of 5 minutes and a beta half-life of 7.5 minutes. After receptor blocking with unfractionated heparin the alpha half-life of the oxidized-LDL tracer was prolonged to 17.5 minutes and the beta half-life to 27.5 minutes. These results indicate that heparin molecules of a comparatively small molecular weight competed the scavenger receptor mediated uptake of oxidized-LDL particles in vivo. Oxidized-LDL particles are known to mediate their pro-atherosclerotic activity in part by stimulating smooth muscle cell proliferation by a scavenger receptor-mediated pathway. It can be speculated, if heparins interfere with the uptake of oxidized-LDL, heparins might thus in part exert their known antiatherosclerotic properties.

Animals↗

PubMed1995

Multistep tumor targeting in nude mice using bispecific antibodies and a gallium chelate suitable for immunoscintigraphy with positron emission tomography.

To improve tumor:tissue ratios in immunoscintigraphy, a three-step targeting method has been developed. The reagents used were (a) a radioactive, low molecular weight chelate prepared from ionic gallium and a phenolic polyaminocarboxylic acid, which can be labeled either with the single-photon emitter 67Ga or with the short-lived positron emitter 68Ga (t1/2 = 68 min); (b) a bispecific monoclonal antibody (bs-mAb) synthesized from the F(ab)2 fragment of the 1.1ASML antibody specific for the glycoprotein CD44v associated with a rat pancreas carcinoma cell line and the F(ab') fragment of an antibody specific for the gallium chelate; and (c) the nonradioactive gallium chelate covalently coupled to transferrin, which served as a high molecular weight blocker to prevent binding of the radioactive gallium chelate to bs-mAbs in the circulation. Targeting experiments in tumor-bearing nude mice with different doses of bs-mAbs, blocker, and 67Ga chelate were adjusted to maximize tumor to tissue contrasts and tumor uptake. Compared with the biodistribution of the 131I-labeled, native 1.1ASML antibody 24 h postinjection, a schedule using 100 pmol bs-mab 24 h later 100 pmol blocker, 15 min later 16 pmol 67Ga chelate, 1 h later examination, increased tumor:blood and tumor: liver ratios by a factor of 5 while keeping the localization of radioactivity in the tumor constant (10.1% injected dose/g). High-contrast images using either 67Ga or 68Ga were obtained within 1 h. The targeting method described enables the use of the short-lived positron emitter 68Ga and thus allows the combination of an improved immunoscintigraphy and positron emission tomography.

Animals↗

PubMed1995

Complexes of a modified low-molecular-weight heparin with protamine are predominantly cleared by a macrophage scavenger receptor-mediated process in rats.

Neutralization of heparin with its antidote protamine is associated with side effects such as pulmonary hypertension. The pharmacodynamic effects of protamine treatment are well documented. However, little is known about metabolic fate of heparin-protamine complexes. Twenty Wistar rats received a 131I-labeled low-molecular-weight heparin tracer intravenously. Four groups of animals were formed: a control group receiving the tracer, a second group receiving protamine after tracer application, a third group receiving maleylated bovine serum albumin (mal-BSA) prior to tracer and protamine injections to inhibit scavenger receptors of the reticuloendothelial system, and the last group receiving preformed heparin-protamine aggregates. All animals were examined by scintigraphy. Blood and tissue samples were analyzed for radioactivity. Protamine injection 2 min after heparin tracer application lead to a rapid decline in blood radioactivity. The radioactivity in the liver increased from 17% for the control to 43% after protamine application. Injection of mal-BSA prior to protamine prevented tracer accumulation in the liver and increased urine excretion (34% versus 20%). In vitro preformed heparin-protamine precipitates were rapidly trapped in the liver. We present evidence that, like the polyanionic heparin, polyanionic heparin-protamine complexes are phagocytosed by a scavenger receptor-mediated mechanism by macrophages, predominantly in the liver. The amount, the size, and the charge density of the complexes might trigger a mediator release from macrophages leading to phenomena such as pulmonary hypertension.

Animals↗

PubMed1995

Evaluation of tumour metabolism and multidrug resistance in patients with treated malignant lymphomas.

The management of patients with treated malignant lymphomas requires functional methods to differentiate a residual soft tissue mass. Patients with treated Hodgkin's lymphoma (HL, n = 20, 68 malignant lesions, three benign lesions) or non-Hodgkin's lymphoma (NHL, n = 26, 46 malignant lesions, one benign lesion) were studied with positron emission tomography (PET) and fluorine-18 deoxyglucose (FDG). Oxygen-15 labelled water was used (n = 14, 25 lesions) in addition to FDG in order to obtain information on the tissue perfusion. Long-term follow-up studies with PET and FDG were performed in nine patients up to 511 days after the initiation of second-line therapy. Fourteen patients underwent single-photon emission tomography (SPET) with technetium-99m sestamibi immediately prior to the first PET examination. PET with FDG displays a high sensitivity for the detection of viable tumour tissue, all the malignant lesions being correctly classified in this study. The possible limitations are inflammatory processes, which may obscure tumour detection due to increased FDG uptake, and malignant lesions with low FDG uptake due to reduced perfusion. Difficulties exist in the prognosis of long-term response, since the change in FDG uptake may be variable. Long-term therapy outcome was correlated with the slope values obtained from the standardized integral uptake (SIU) data, which provides a new approach for the evaluation of PET follow-up studies. 99mTc-sestamibi, which should reflect the multidrug resistance, was evaluated with respect to therapy outcome. A high uptake of 99mTc-sestamibi was observed in patients with stable disease or better. The data support the hypothesis that sestamibi may reflect multidrug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Stereotactically guided fractionated radiotherapy: technical aspects.

A system for high precision radiotherapy in the head and neck region has been developed. The components of the system are a head mask connected to a stereotactic frame, a localization unit that can be used during CT- and MR-imaging and a stereotactic target positioner. Conformal precision radiotherapy is planned with a new treatment planning system (Voxelplan-Heidelberg). Three different multi-leaf collimator systems are used. An evaluation of the precision and accuracy of the head fixation system, which was performed with a photogrammetry system, is presented.

Head↗

PubMed1993

Altered pharmacokinetic properties of a lipophilically derivatized low-molecular-weight heparin in rats.

A new generation of lipophilic heparins has been developed that show longer-lasting inhibitory effects on the coagulation system. We have studied the radiopharmacokinetics of a derivatized low-molecular-weight heparin (LMWH) with a residualizing lipophilic tyramine-deoxysorbitol label in comparison with conventional LMWH after intravenous application into Wistar rats. Whole body scintigraphy and analysis of the blood and organ distribution of different tracer preparations revealed that the lipophilically derivatized LMWH substance was predominantly trapped in the liver RES by a scavenger receptor-mediated mechanism. After the saturable uptake mechanism was blocked by maleylated bovine serum albumin, 41.4% of the lipophilic LMWH tracer circulated in blood, as compared with 18.4% of the control and 1% of conventional LMWH. The same results were attained by a competition experiment with an excess of unfractionated heparin. Urinary excretion of the lipophilic tracer among the rats in this competition experiment was considerably lower (13.7%) as compared with conventional LMWH (53.0%). Experiments with lipophilic LMWH tracer bound nonspecifically to rat serum albumin confirmed that the prolonged half-life might in part be due to an increased affinity for albumin. About 59% of the activity of the lipophilic tracer bound to albumin was found in the liver reticuloendothelial system, and only 3.3% were excreted to urine 3 hours after injection. Further studies are necessary to evaluate the accumulation rates and the metabolic fate of lipophilically derivatized heparins in the case of an impeded reticuloendothelial system uptake before attempts are made to therapeutically apply these compounds.

Albumins↗

PubMed1992

Design of compounds having enhanced tumour uptake, using serum albumin as a carrier--Part II. In vivo studies.

In the present in vivo study the uptake kinetics of radioiodinated albumin were determined in normal organs, and tumours of rats using sequential scintigraphy. Rat serum (RSA) was radioiodinated either directly at a tyrosine residue (d-RSA), or indirectly at a residualizing marker tagged to the albumin (rm-RSA). These labelling procedures did not alter the kinetics of labelled albumin, as shown by blood disappearance curves. Directly labelled albumin was shown to have tumour uptake. Residualizing markers like tyramine-cellobiose (TCB), tyramine-deoxysorbitol (TDS) and aminonaphthaltyrimide-deoxysorbitol (ANTDS) are metabolically inert. After the intracellular degradation of the albumin carrier the TCB-, TDS- and ATNDS-residues accumulate in the lysosomes, particularly those of tumour cells. It was able to be demonstrated that residualizing-marker tagged albumin-bound radioactivity was five times higher after 72 h than the tumour radioactivity after use of directly labelled RSA. These data found support when whole-body retention of directly labelled RSA, and residualizing marker-RSAs, were determined. After 72 h, 60% of 131I bound to RSA directly had been excreted, compared to only 25% of the activity attached indirectly to RSA with a residualizing marker. Whole-body autoradiography of rats injected with directly labelled RSA, or residualizing marker-RSA, support these results. Most of the radioactivity of directly labelled RSA was excreted within 24 h, whereas labelled residualizing marker-RSAs were also stored in tumour and liver tissue. ANTDS bound to RSA allows fluorescence microscopy. Cryosections of tumours from rats preinjected 10 min and 24 h with ANTDS-RSA before dissection, demonstrated that the fluorescence is localized on and in tumour cells. This indicates that cellular uptake of the marker takes place. Fluorescence was not observed in muscle tissue. This appears to suggest that the albumin uptake is greater in tumours than in normal tissue, and that it is metabolized in the tumour cells.

Animals↗

PubMed1992

A bifunctional HBED-derivative for labeling of antibodies with 67Ga, 111In and 59Fe. Comparative biodistribution with 111In-DPTA and 131I-labeled antibodies in mice bearing antibody internalizing and non-internalizing tumors.

To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than 111In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with 67Ga, 111In and 59Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of 131I and 111In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for 67Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel 131I clearance after administration of 131I-MAbs, while 111In-HBED-CI-labeling led to a constant 111In liver level quite similar to that of 111In-DTPA-MAbs. In tumors, 67Ga-HBED-CI-MAb uptake again paralleled that of 131I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. 111In of 111In-HBED-CI- and 111In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with 111In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with 67Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of 67Ga-HBED-CI-, 111In-HBED-CI- and 111In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.

Animals↗

PubMed1992

Hepatic uptake of a modified low molecular weight heparin in rats.

Fractionated and unfractionated heparins are widely used as antithrombotic agents. Because of their heterogeneous composition, it is difficult to study the pharmacokinetics of these drugs. We now report on a new method for labeling low molecular weight heparins with 131I by binding tyramine to the anhydromannose end of the molecules. We examined the pharmacokinetics of the compound by intravenous injection of 131I-tyramine-heparin into Wistar rats. About 18% of the activity was found in the liver, whereas 33% was detected in urine. Biological activity in terms of Factor Xa inhibition was measurable. Since evidence from cell culture experiments implies that reticuloendothelial cell system receptors might be involved in heparin metabolism, maleylated BSA, a substance known to block scavenger receptors, was injected before the radiolabeled heparin compound. The liver uptake was reduced from 17.4 to 4.8%. Injection of unfractionated heparin before tracer application caused a considerable increase in urine excretion of the tracer substance. To our knowledge, this is the first report that liver uptake of heparins is linked to scavenger receptor mediated mechanisms in vivo. This interaction of heparins with scavenger receptors might play an important role in the biology of the vessel wall.

Animals↗

PubMed1992

Establishment and characterization of monoclonal antibodies against an octahedral gallium chelate suitable for immunoscintigraphy with PET.

As a prerequisite for preparing bispecific antibody conjugates containing anti-tumor and anti-metal chelate binding sites that can be used for pretargeted immunoscintigraphy, monoclonal antibodies (Mabs) have been raised against an octahedral metal chelate synthetized from gallium (Ga) and the hexadentate ligand N,N'bis[2-hydroxy 5-(ethylene beta carboxy) benzyl] ethylenediamine N,N' diacetic acid (Ga-HBED-CC). With use of the Farr assay, binding studies with the 67Ga-labeled chelate and three clones of anti-chelate Mabs showed that none of the Mabs were able to precipitate more than 50% of the Ga-chelate, suggesting an enatiomerism of the Ga-chelate and a sensitivity of the Mabs to either one or the other chelate enantiomer. This could be confirmed by comparing the circular dichroism spectra of the Ga-chelate fractions that passed affinity columns containing the Mabs immobilized on sepharose without retention. With use of a Ga-HBED-CC enantiomer, whole-body retention in mice, preinjected with the corresponding anti-metal chelate Mab of ca. 70% ID, was measured compared to 2.1% retention in mice not preinjected with the Mab. Due to the high affinity of chelate-to-Mab binding in vivo, bispecific antibody conjugates prepared from the fragments of the anti-Ga-chelate Mab might be suitable for pretargeted immunoscintigraphy with the short-lived positron-emitter 68Ga.

Animals↗

PubMed1990

Investigations concerning the potential for using 1H NMR relaxometry or high-resolution spectroscopy of plasma as a screening test for malignant lung disease.

In 158 plasma samples, obtained from patients with lung carcinoma, lung metastases, and infectious or inflammatory lung diseases and from healthy controls, the NMR relaxation times T1 and T2 of water protons were measured at a resonance frequency of 20 MHz by pulsed NMR techniques and adjusted to a standardized total plasma protein concentration. For one-third of these samples water-suppressed 500-MHz 1H NMR spectroscopy at 37 degrees C was used (a) to determine the widths of the composite lipid methyl and methylene signals, and (b) to quantitate individual lipid methylene signal components that could be detected in resolution-enhanced spectra. In addition, hematological parameters and the plasma levels of several acute phase proteins and apolipoprotein-A were monitored. No diagnostically significant differences between lung carcinoma patients and patients with nonmalignant lung disease could be found for any of the plasma NMR parameters, nor could T1 or lipid linewidth data distinguish between any patient group and healthy controls. However, the mean T2 was significantly shortened by about 15% for any kind of lung disease compared to healthy controls. Similar but less significant results were found for apolipoprotein-A levels. A linear discriminant function, calculated from the apolipoprotein-A and T2 data, did not improve the differentiation between malignant and nonmalignant lung disease but did improve the discrimination between tumor patients and healthy controls up to a sensitivity and specificity of 80 and 96.5%, respectively. T2 correlates inversely with plasma fibrinogen levels and the blood sedimentation rate and, therefore, appears to monitor a general inflammatory status of a tumor patient rather than the presence or absence of cancer. For all groups except healthy pregnant women, the lipid methylene composite signal linewidth correlates inversely with the fraction of mobile triglyceride present (mainly as VLDL), as estimated from resolution-enhanced spectra.

Blood Proteins↗

PubMed1990

Design of compounds having an enhanced tumour uptake, using serum albumin as a carrier. Part I.

The search for a radioiodinated "cumulative" protein label, stored within cells following intracellular protein degradation, suggested that plasma protein turnover of tumours might be of use. While earlier investigators were primarily interested in metabolism and utilization of plasma proteins by tumours, we tried to utilize the tumour protein turnover to channel radioiodine labelled compounds, covalently bound to serum albumin, into neoplastic tissues. To identify those parameters which influence the tumour uptake and storage, we investigated a series of compounds having different chemical and physicochemical properties. Unbound, small molecular weight compounds were rapidly eliminated from the circulatory system. They had a prolonged biological half life if linked to serum albumin (SA), especially when derivatized with deoxysorbitol. Parallel with the prolongation of the biological half-life we noted a remarkable increase in tumour uptake, which was not accompanied by increased liver activity. Furthermore, without thyroid blockade, we failed to detect significant radioiodine uptake in this organ after 24 or 72 h. This is due to the particular coupling mechanism, which may be relevant for other (radio)iodinated pharmaceuticals used in medicine. Glucose and aromatic amines, as well as aromatic aldehydes and glucamine react to form deoxysorbitol derivates, which then have similar biokinetics after linkage to serum albumin. This indicates that a new approach in tumour detection and possibly in tumour therapy may be possible when SA is used as a carrier molecule, using the described labelling procedure.

Animals↗

PubMed1990

Synthesis of positively charged phthalocyanines and their activity in the photodynamic therapy of cancer cells.

Positively charged zinc containing or metal free phthalocyanines 6a-c and 7a-c were prepared via a three step procedure starting from 4-nitrophthalonitrile. The phthalocyanines contain alkyl chains of different length in order to influence the hydrophilic vs lipophilic character of the compounds. The partition between a hydrophilic (water) and lipophilic (octanol-1) phase was determined, and the photoredox activities were investigated. Initial results on the photodynamic activity of these compounds were compared with those of Dougherty's Photofrin II on different malignant and non-malignant cell lines (XP 29MAmal, CX1, HeLa, S180 and NO17). Positively charged phthalocyanines in vitro showed a higher photodynamic activity than Photofrin II.

Animals↗

PubMed1990

Uptake of indium-111 in the liver of mice following administration of indium-111-DTPA-labeled monoclonal antibodies: influence of labeling parameters, physiologic parameters, and antibody dose.

Liver uptake of indium-111 (111In) in mice was investigated following administration of 111In-DTPA murine monoclonal antibodies (111In-DTPA-MAbs) labeled by the cyclic anhydride method. Biodistribution of HPLC-purified 111In-DTPA-MAb preparations was checked with a low (0.2 micrograms) and a high (8.0 micrograms) MAb dose. Using Bio Gel P-30 for desalting the MAb-conjugates, 111In uptake in the liver amounted to 8%-9% of the injected dose (ID) and was independent from the MAb dose, the DTPA-to-MAb molar ratio, tumor growth and biologic variability (different MAbs and different strains of mice). Using Sephadex G-25 for desalting, 0.2 micrograms doses from 7 out of 26 preparations showed increased liver accumulation of 111In in non-tumor mice ranging from 15%-25% of ID. Corresponding high doses led to a "normal" value of 8%-9%. Increased liver uptake of the low dose could not be reduced by coadministration of the unconjugated MAb, but was normal after reinjection of "in vivo filtered" material. An inverse intracellular distribution of 111In activity between sediment and supernatant of liver homogenates, following the administration of the low and the high MAb dose, indicated an artifact of the labeling procedure rather than an inherent biological property of labeled MAbs.

Animals↗

PubMed1988

Regional myocardial nitrogen-13 glutamate uptake in patients with coronary artery disease: inverse post-stress relation to thallium-201 uptake in ischemia.

The purpose of the present study was to evaluate the clinical significance of myocardial scintigraphy with nitrogen-13 (N-13) glutamate as a marker of myocardial metabolism. Within 2 weeks after cardiac catheterization, 25 patients with single vessel left anterior descending coronary artery disease underwent thallium-201 imaging (5 min and 3 h after injection) and N-13 glutamate scintigraphy (10 min after injection). Radionuclide studies were performed in the 30 degrees left anterior oblique projection after symptom-limited bicycle exercise, and regional tracer uptake was quantified by computer-assisted placement of regions of interest within the regions of myocardial activity. Poststenotic tracer uptake in the perfusion bed of the left anterior descending coronary artery (septum) was then normalized to the tracer uptake in the nondiseased left circumflex territory (posterolateral segments = 100%). In 14 patients with a history of previous myocardial infarction (Subgroup A), deficient poststenotic N-13 uptake correlated closely with thallium-201 uptake in both initial (r = 0.82, p less than 0.001) and redistribution (r = 0.74, p less than 0.01) scintigrams. By contrast, in 11 patients with no previous myocardial infarction and normal left ventricular function at rest (Subgroup B), initial uptake of both tracers was inverse: poststenotic N-13 glutamate uptake increased with decreasing thallium-201 uptake during exercise-induced ischemia (r = -0.64, p less than 0.05) and was closely correlated with the percent thallium-201 redistribution (r = 0.74, p less than 0.01). Thus, augmented accumulation of N-13 glutamate in reversibly ischemic (that is, viable) myocardium, and decreased uptake in myocardial scar tissue suggest the clinical usefulness of this metabolic tracer in the differentiation between viable (metabolically active) and irreversibly damaged myocardium.

Coronary Disease↗

PubMed1987

NMR relaxation times T1 and T2 of water in plasma from patients with lung carcinoma: correlation of T2 with blood sedimentation rate.

The T1 and T2 NMR relaxation times of water protons in plasma, obtained from patients with lung carcinoma, healthy volunteers, and patients with nontumor diseases were measured at a resonance frequency of 20 MHz. Additionally hematologic parameters were determined. In tumor patients the mean plasma T2 was shortened by about 20%, and an increase in the blood sedimentation rate (BSR) was noted. Similar but less pronounced results were found for the nontumor group of patients, indicating that the shortening of T2 in plasma is a secondary host response. However, a plot of plasma 1/T2 versus BSR from tumor patients showed a significant correlation between these two parameters. No such correlation could be detected in the nontumor group of patients. The correlation of 1/T2 with BSR, found solely in the tumor patient group, increased the diagnostic sensitivity of T2 measurements and may help to differentiate between malignant and nonmalignant disease. No significant variation in the T1 spin-lattice relaxation time was observed.

Adult↗

PubMed1986

Labeling of monoclonal antibodies with a 67Ga-phenolic aminocarboxylic acid chelate. Part I. Chemistry and labeling technique.

As a chelating agent for labeling antibodies (Abs) with metallic radionuclides, a propionic acid substituted ethylenediamine N,N'-di-[(o-hydroxyphenyl) acetic acid] (P-EDDHA), which tightly complexes 67Ga, was synthesized. The 67Ga-P-EDDHA chelate was coupled in aqueous solution to IgG at a molar ratio of 1:1 via carbodiimide. The average coupling yield was 15%. A specific activity of 4 mCi/mg IgG could be obtained with commercially supplied 67Ga. In vitro stability was evaluated in human serum at 37 degrees C and showed a half-life of about 120 h for the release of 67Ga from the labeled Ab during the initial phase of incubation. This in vitro halflife is similar to that measured for 111In-DTPA labeled Abs. Because of the high stability of the 67Ga-P-EDDHA chelate, the in vivo formation of radioactive labeled transferrin by transchelation, as described for 111In-DTPA labeled Abs, should, however, be reduced by this labeling technique.

Animals↗

PubMed1986

A new radioiodine exchange labeling technique.

A new technique of radioiodine exchange labeling is presented. The method was developed with respect to the short physical half lives of 123I and 121I, the altered activity concentrations and varying impurities, which hamper the previously introduced labeling methods. The described "one step reaction" is applicable to a series of organic compounds with different physicochemical and physiological behaviour as well as to all radioisotopes of iodine.

Half-Life↗