5. Diagnostic uses of radioactive microspheres
Diagnostic studies with radiopharmaceuticals include dynamic and static imaging and in vivo function tests. Dynamic imaging provides information about the biodistribution and pharmacokinetics of drugs in organs. Performed with a g-camera, dynamic studies are generally carried out over a pre-set length of time and provide clues to the functioning of the organ being examined. Static imaging, on the other hand, provides morphological information about an organ such as its shape, location and size. Furthermore it allows the exact location of tumours to be determined. Static imaging, unlike dynamic imaging, is normally done at a single point in time, with the imaging time being dependent on the organ activity. In contrast to dynamic and static imaging, in vivo function tests do not require imaging. Instead they are evaluated by comparing an injected or swallowed amount of radioactivity to the measured radioactivity in urine or blood.
All three types of diagnostic studies can be performed with radioactive microspheres which contain one or several -emitters that can be detected by a g-camera. The first such "microspheres" in clinical use were red and white blood cells, which were taken from a patient, labelled with 111In or 51Cr, and then re-injected. Red blood cells labelled with 51Cr are commonly used for the measurement of red blood cell mass and for imaging of the spleen. For the latter purpose, the red blood cells are denatured by heating, which renders them spheroidal and nondeformable, and makes them easy to take up by the spleen. Another common application of radiolabelled red blood cells is the accurate determination of total systemic arterial blood flow or venous return, as well as, for blood flow determination within specific organs . These blood flow parameters are important when drugs for the treatment of cardiovascular diseases are evaluated. White blood cells labelled with 111In-oxine are used for the detection of inflammatory diseases, abscesses or other infections. A less expensive method has been developed in which the neutral and lipophilic 99mTc-HMPA0 complex is prepared from a kit and then incubated with the leukocytes . Platelets labelled with "'In are also used to detect actively forming deep vein thrombi, to measure blood flow, and to detect regions of infection . Radiolabelled blood cells are still used today, although premade radioactive microspheres containing several different y-emitters (see Table 7) are easier to use and do not require time-consuming labelling procedures . Unfortunately, the radioactive microspheres of homogenous size are made from polystyrene and thus are not biodegradable, making them inappropriate for clinical use.
For the diagnosis of pulmonary embolism, both the inhalation of small, radioactive 99mTc-carbon particles (Technegas) and the perfusion of the lung with 99mTc-labeled albumin particles are used. In the first case, Technegas behaves, due to the small particle size of less than 100 nm, much more like a gas than a radioaerosol and diffuses into the entire accessible lung volume. In the second case, macroaggregated albumin is mainly used for the quantification of shunts associated with intrapulmonary arteriovenous malformations and the diagnosis of pulmonary diseases such as cancer and hypertension (Figure 5). The diagnostic determination of shunts within an organ is generally done prior to using radioactive microspheres in radioembolization therapy (see below)  in order to prevent radiotoxicity to the lungs . The biological halflife of the albumin particles is only 1 to 3 hours, so any therapeutic interventions can easily be performed afterwards.
Table 7: Radioactive microspheres for diagnostic applications
Type ofradioactive microspheres used
Gated blood pool study mIn- or 51Cr-labeled red blood cells
Thrombus imaging in deep vein thrombosis
Blood flow measurements
Investigation of biodistribution and fate of (drug-loaded) microspheres
Liver and spleen imaging
111In-labeled platelets 99mTc-macro-aggregated human serum albumin (MAA) 99mTc-sulfur colloid
Polystyrene-microspheres labelled with thegg-emitters 141Ce, 57Co, 114mIn, 85Sr, 51Cr, and others (animal experiments)
3H, 14C-labeled microspheres (animal experiments)
Tc-impregnated carbon particles (= Technegas)
99m Tc-macro-aggregated human serum albumin (MAA)
99mTc-macro-aggregated human serum albumin (MAA)
99mTc-macro-aggregated human serum albumin (MAA) 99mTc-sulfur colloid 99mTc-tin colloid
Bone marrow imaging 99mTc-sulfur colloid mTc-antimony sulphide colloid
all sizes 11.4 ^m
Table 7: Radioactive microspheresfor diagnostic applications
Type of radioactive microspheres used
Gastrointestinal transit studies
'''In-labeled leukocytes mIn-labeled liposomes 99mTc-labeled liposomes 99mTc-albumin nanocolloid
99mTc-labeled liposomes 67Ga-NTA- or111 In-NTA-labeled liposomes
99m Tc-sulfur colloid "'in-labeled ion exchange resins
Local restenosis prevention in coronary arteries
141Ce microspheres (preliminary imaging tests)
For liver, spleen, bone marrow and lymphatic system imaging, colloidal microparticles, such as 99mTc-sulfur colloids, are most useful (Table 7). To illustrate, Figure 6 shows the changes in a cirrhotic patient made visible by 99mTc-sulfur colloid. The lymphatic system can also be imaged or targeted with drugs through the use of the poly(lysine) nanospheres . The ideal nanospheres for this purpose are 10-30 nm, contain carbohydrate groups on the surface, and are able to bind the g-emitter mIn via the covalently bound chelator DTPA.
The radiopharmaceutical 99mTc-sulfur colloid is also used for gastrointestinal blood loss studies, for the preparation of a 99mTc-labeled egg sandwich for gastric emptying studies , and for the determination of oesophageal transit and gastro-oesophageal reflux. For colonic transit studies, radioisotopes with a half-life longer than 99mTc are more appropriate, and 111In-labeled ion exchange resins, but also 131l-cellulose are utilised . Latex-particles of 2.5 ^m size and labelled with 99mTc have also been shown to give excellent abdominal images . In all these gastrointestinal transit time studies, the size of the radiolabelled microspheres does not influence the measured times.
Radiolabelled liposomes, another diagnostic class of radioactive particles, has been used for tumour imaging since 1977. In order to prolong the blood residence time and maximise tumour uptake, neutral, positively and negatively charged small unilamellar vesicles (= SUV's) of 65 nm encapsulating 111In were made and their biodistribution measured in mice . The highest uptake of 18.5% of injected dose per gram of tumour was measured with the neutral liposomes. A further attempt to minimise the high blood-background radioactivity levels was to inject 67Ga- or 111In-labeled liposomes containing biotin groups on their surface and then chasing the non-tumour bound liposomes 2 hours later with avidin . This chase removed the unbound liposomes effectively from the circulation and the blood concentration of the radioactive liposomes dropped to a tumour-to-blood ratio of about 15 to 1 shortly after the avidin chase. The avidin-biotin-liposome conglomerates accumulated in the liver and increased the liver activity about 2.5 fold.
Radiolabelled microspheres can also be used to image cancer lesions. An interesting application is the use of PLA-microspheres labelled with 131T-iopanoic acid derivatives for the imaging of liver tumours . The normal liver parenchyma lined with Kupffer cells takes up the microspheres, but the cancer lesions do not possess fixed macrophages and therefore exclude the radioactive microspheres, showing the focal lesions as defects. The recently introduced 99mTc-PLA microspheres which were radiolabelled in a SnCk-containing kit could be used for the same application , although the stability described as "more than 80% bound after 6 hours" is not optimal yet.
The in vivo faith of microspheres after intra-arterial catheter-mediated delivery through a porous balloon to a rabbit's femoral artery has been investigated with radioactive 141Ce-microspheres . Although only 0.14% to 0.16% of the microspheres were delivered to the vessel wall, an average of 92% of these microspheres was still present 7 days later. In addition, much higher amounts of the microspheres were found in the periadventitia (the vessel's "outside") and the overlying musculature and are believed to be caused by the increase of vaso vasora present in atherosclerotic patients. Although the targeted amounts of microspheres are small, they can lead to drug concentrations a few hundred times higher than the serum concentrations, allowing for effective restenosis therapy with microspheres containing cytostatic or antiproliferative agents, especially from the periadventitia side.
Many radiolabelled particles, microspheres and liposomes are appropriate for therapy once the encapsulated diagnostic radioisotope has been exchanged for a therapeutic one from the a- or b-emitter group. Typical uses in the last 20 to 40 years include local applications for the treatment of rheumatoid arthritis, liver tumours and cystic brain tumours. However, their use remains experimental because of smaller than expected target uptake, unwanted toxicity and insufficient treatment effects that have resulted from radiochemical instability and suboptimal biodistribution of the radiopharmaceutical. In addition, there exists a general negative attitude towards the use of radioactive substances in spite of proven superior results of many radiation therapies [102-104]. What follows is a review of a few a-emitter applications as well as the more established b -emitter therapies.
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