Buck A. Rhodes

Preparation of metabolizable radioactive human serum albumin microspheres for studies of the circulation

Abstract Radioactive μspheres have been prepared from human serum albumin (HSA) in sizes between 12 and 44 &μ;. These μspheres are degraded within the body after injection. The rate of degradation can be varied by changes in the method of preparation. The μspheres can be easily labeled with various radionuclides. When injected intravenously, more than 90 per cent of the μspheres are extracted by the capillary bed of the lungs. HSA μspheres have advantages over other particles that are now being used for studies of the circulation.

RADIOACTIVE ALBUMIN MICROSPHERES FOR STUDIES OF THE PULMONARY CIRCULATION.

Since its introduction into clinical medicine in 1963 (12), lung scanning has become a widely used method for determining the distribution of pulmonary arterial blood flow (13). The most common radiopharmaceutical for this purpose is 131 -labeled macroaggregates of human serum albumin (MAA), but more recently both 113mIn-labeled floes of iron hydroxide (10) and 99mTc-labeled MAA (4) have also been used. Attempts to extend the labeled particle distribution method to the study of the systemic circulation and to the measurement of arteriovenous shunting have failed because these particles are too irregular in size and too fragile (5). Such studies have been carried out in experimental animals with labeled ceramic or carbonized microspheres (2, 5, 7–9, 11). Although these microspheres have been used in man for in situ radiation therapy (1, 14), they have not been employed in diagnostic studies because they are not metabolized. To extend the methods which employ radioactive microspheres to the study of the hum...

Considerations in the radiolabeling of albumin

Labeled albumins for blood-pool, albumin-metabolism, and gastrointestinal-blood-loss studies have been readily available for years, and their clinical use is well established. Labeled albumin for cisternography was once widely used; now it is restricted due to pyrogen contamination at levels too low to be detected by the official U.S.P. pyrogen test but still high enough to cause a significant incidence of aseptic meningitis when injected intrathecally. The more sensitive Limulus test for pyrogens may be used to overcome this problem. Labeled albumin for nuclear angiogrophy and gated cardiac blood-pool studies is presently limited to 99m Tc-albumin. Lack of a commercially available radiopharmaceutical for this purpose has been a limiting factor in the clinical application of these studies. Kits can be used to prepare 99m Tc-albumin from 99m Tc generator eluates, but they have not yet been perfected to the point where radiochemical contaminants are not a problem. Unbound pertechnetate and insoluble technetium cause unnecessary degradation of resolution and prolongation of the studies. This problem can be solved by daily quality-control testing of kit preparations or by the development of commercial sources of prelabeled and pretested 99m Tc-human serum albumin.

Experimental radiotherapy of receptor‐positive human prostate adenocarcinoma with 188Re‐RC‐160, a directly‐radiolabeled somatostatin analogue

The therapeutic potential of the somatostatin analogue RC‐160 radiolabeled with 188Re was evaluated in nude mice bearing xenografts of human prostate adenocarcinoma. 188Re‐RC‐160 was selectively retained in both DU‐145 and PC‐3 tumors following direct intra‐tumor injection at all time points examined (2, 6 and 24 hr post‐injection). Unbound 188Re‐RC‐160 was rapidly excreted via the hepatobiliary system and, with the exception of the gastrointestinal tract, very little normal organ uptake was found at any time point examined. Negative control compounds, 188Re‐perrhenate and 188Re‐mercaptoacetyl‐triglycine (188Re‐MAG3), were essentially washed out of the tumor by 6 hr post‐injection and were rapidly excreted through the kidneys. 131I‐RC‐160, used as a reference compound, had a biodistribution in tumor‐bearing animals similar to that of 188Re‐RC‐160. In PC‐3 xenografts, 188Re‐RC‐160 gave a dose‐dependent therapeutic response (stasis or regression) even in animals with relatively large tumor masses (greater than 600 mm3), whereas the macro‐aggregated form of 188Re‐RC‐160 did not. Long‐term studies with 188Re‐RC‐160 demonstrated a protracted reduction of tumor volume and a positive effect on animal survival. Neither RC‐160 by itself nor a 188Re‐labeled peptide, unrelated to somatostatin (PA‐22‐2, a laminin peptide), demonstrated the reduction in tumor mass observed with 188Re‐RC‐160. 188Re‐RC‐160 shows potential as a new clinical agent for treatment of somatostatin‐receptor‐positive cancers.

Absence of Anatomic Arteriovenous Shunts in Paget's Disease of Bone

Abstract To determine whether anatomic shunting through arteriovenous (AV) anastomoses is responsible for the circulatory abnormalities associated with Pagets disease of bone, shunting of particles, 15 to 30 μ in diameter, was measured in nine patients. In addition, relative regional perfusion, radiographs and serum alkaline phosphatase were measured. Hemodynamic data were obtained in three of the patients. No AV shunting was found, despite the fact that blood flow to the involved bone was increased in every case and AV oxygen differences were decreased in some. We therefore conclude that hyperperfusion of diseased bone rather than AV shunting is responsible for the hyperkinetic circulation and decreased AV oxygen differences in patients with Pagets disease of bone.

Lung scanning with 99mTc-microspheres.

99mTc-labeled human serum albumin microspheres have now been used to obtain 1,464 lung scans in 1,052 patients and normal subjects, some patients receiving 10 or more serial injections. The microspheres were prepared, sized, and tested for quality control, then labeled with the radionuclide just prior to use, In 5 patients minimal reactions were observed. The scans were comparable and usually superior to those obtained with previously used radio-pharmaceuticals.

Scanning of Thromboemboli with 131I-Streptokinase

Thromboemboli were localized in dogs by intravenous injection of 131I-streptokinase. Thrombi tagged with 99mTc microspheres were released into the bloodstream. The dots were localized with a 99mTc scan, after which the dogs were given 131I-streptokinase and rescanned for 131I radioactivity. In the locations previously shown by the 99mTc scan.

Radiolabeled streptokinase and urokinase and their comparative biodistribution

Abstract Streptokinase and urokinase were labeled with I-131 and Tc-99m. For iodination the chloramine-T method was used, and Tc-99m labelling was carried out in the presence of stannous ion. Thin layer chromatography and gel filtration showed a high labelling ratio, and autoradiography following immunoelectrophoresis showed the radioactivity over the bands corresponding to the enzymes. One hour tissue distribution study in mice showed the differences in the biological behavior of these radiopharmaceuticals. Clearance studies in dogs showed relatively faster clearance of urokinase with higher urinary excretion compared to streptokinase with minor differences between I-131 and Tc-99m labeled products.

A Preliminary Report on the Complementary Roles of Arteriography and Perfusion Scanning in Assessment of Peripheral Vascular Disease

The evaluation of peripheral vascular disease in man includes various clinical and radiographic procedures. Arteriography is useful in the detection of gross anatomical changes but does not provide information about muscle perfusion. 99mTc-labelled microspheres were utilized in 50 patients to evaluate extremity perfusion patterns and to provide a qualitative assessment of muscle perfusion. Correlative studies were carried out comparing perfusion scans with clinical history, arteriographic findings and surgical results.

The use of Limulus testing to reduce the incidence of adverse reactions to cisternographic agents

The temperature records of 30 patients were examined for a febrile response after the injection of 111ln-DTPA for cisternography. All lots of the material were tested and found to be negative by the U.S. Pharmacopeia rabbit test for pyrogens. The material also was tested for reactivity with the amebocyte lysate of Limulus. Six of the seven patients who received material strongly reactive with the Limulus lysate had temperature increases greater than 1°F within eight hours of the injection. No febrile response was observed in the remaining patients, who received material weakly reactive or nonreactive with the Limulus lysate. In two of the seven patients who received the strongly reactive material, aseptic meningitis also developed. This observation supports the hypothesis that bacterial endotoxin contamination of radiopharmaceuticals used in cisternography may cause aseptic meningitis.