Fast Blood Clearance Research Articles

Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients.

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

Simultaneous study of the biodistribution of radio-yttrium complexed with EDTMP and citrate ligands in tumour-bearing rats

The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. 88Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like 90Y, 169Yb, 225Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.

Selection of a dtpa chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice

Our previous studies with a 90Y-labelled antibody against carcinoembryonic antigen (CEA) conjugated to the cyclic anhydride-DTPA (CA-DTPA) indicated that the accretion of 90Y in the bone may limit the application of 90Y-labelled antibodies for therapy. In this report, we have compared the tumor targeting of CA-DTPA-conjugated antibody to antibody conjugated with 4 isothiocyanatobenzyl (ITC-Bz) derivatives of DTPA in nude mice bearing a human colonic tumor xenograft. In biodistribution studies using an 111In-labelled anti-CEA murine monoclonal antibody (MAb), the CA-DTPA-conjugated MAb showed lower tumor uptake, faster blood clearance, and higher accretion in the liver than any of the 4 ITC-Bz-DTPA-conjugated MAbs. There were smaller differences among the 4 ITC-Bz-DTPA conjugates. Whole-body autoradiography of animals given 90Y-MAb prepared with the CA-DTPA or the ITC-Bz-DTPA showed less radioactivity in the bone with the ITC-Bz-DTPA-MAb than the CA-DTPA-MAb. 90Y uptake in the bone corresponded with regions of low proliferative activity as defined by 3H-labelled thymidine, suggesting that the 90Y was in the cortex rather than the marrow. These studies clearly show an advantage of the ITC-Bz-DTPA derivatives for 90Y and 111In labelling of MAbs.

Pharmacokinetics, biodistribution and dosimetry of 99Tcm(V)DMSA in humans with squamous cell carcinoma

Technetium-99m (99Tcm)(V) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to evaluate squamous carcinoma (SCC) of the head and neck. This study evaluated the pharmacokinetics and biodistribution of 99Tcm(V)DMSA in patients with SCC and calculated the bone mass of a New Zealand White (NZW) rabbit. This data was then used to calculate the effective dose equivalent in man. A total of 16 patients were studied (5 with no tumour, 11 with tumour). 99Tcm(V)DMSA had a fast bi-exponential blood clearance in patients with no tumour (30 and 401 min) and patients with tumour (30 and 387 min) with no significant difference (p greater than 0.05) between the two groups. 99Tcm(V)DMSA had a fast cumulative urine excretion with mean half-times in non-tumour and tumour patients of 183 min and 244 min respectively. There was no significant difference (p greater than 0.05) between these two latter groups. The effective dose equivalent of 99Tcm(V)DMSA in man is 5.1 microSv/MBq.

A Preliminary Study of Brain Gliomas with H17E2 Monoclonal Antibody: Immunoscintigraphy and Pharmacokinetics

Ten patients with relapsing high grade brain gliomas and one patient with low grade glioma were studied with a monoclonal antibody (H17E2) against placental alkaline phosphatase. In addition 2 patients with relapsing high grade glioma were studied with a non specific antibody (4D513/2118). 1 mCi of Iodine-131-labelled H17E2 was administered intracarotidly (i.c.) in two, and intravenously (i.v.) in 9 patients. Immunoscintigrams were taken at 0, 2, 24, 48 and 72 hours. Radioactivity was monitored in blood and urine. Tumour/non-tumour ratios were estimated (max. 2.45). All high grade gliomas receiving specific antibody irrespective of the route of administration, gave a positive immunoscintigraphic pattern, increasing in intensity with time. Disappearance of radioactivity in blood was biexpontential with a long component over 30 hours. Urinary excretion of radioactivity ranged from 3.7-21.7% of administered dose/day. The patient with low grade glioma and the patients receiving non specific monoclonal antibody showed a negative pattern, a fast blood clearance and a high urinary excretion. We conclude that a) Iodine-131 labelled H17E2 proved to be stable in vivo and produced satisfactory tumour localisation and b) i.v. route was as good as i.c.

Monoclonal antibodies to placental alkaline phosphatase: preclinical evaluation in a human xenograft tumour model of F(ab')2 and Fab fragments.

Six new placental alkaline phosphatase monoclonal antibodies (MAbs) have been evaluated in order to select a potentially clinically useful antibody fragment for use in immunoscintigraphy or therapy. Initially, 3 antibodies were identified by trial pepsin digestion as likely to give satisfactory F(ab')2 yield. The corresponding intact antibodies were then compared for ability to localise human xenograft tumours in athymic mice. Of the best of these, designated 3F6, F(ab')2 and Fab fragments were then evaluated in similar xenograft experiments. In intact antibody biodistribution comparisons, 3F6 showed good tumour retention and satisfactory specific/non-specific ratios at 8 days. In similar fragment biodistribution experiments 3F6 F(ab')2 gave the highest tumour/blood ratio (10) and tumour/organ ratios (19) and the best specific/non-specific localisation. This fragment also showed higher absolute uptake in the tumour than intact antibody, 18.9% and 14.4% respectively of the injected dose. As expected, fragments showed much faster blood clearance rates than whole antibody. For Fab the in vivo instability by 6 hr was also demonstrated.

Labeling of sarcoma associated monoclonal antibody with 111In, 67Ga and 125I

Labeling of human sarcoma-associated murine monoclonal antibody (MAb) 23H7 with 67Ga and 111In by the bifunctional ligand method is reported. 67Ga was chelated to the MAb via desferrioxamine B and 111In via the cyclic anhydride of DTPA. Higher specific activity was obtained with 67Ga (4-5 microCi/micrograms) as compared with 111In (2 microCi/micrograms). The binding capacity of the MAb was confirmed by repeated indirect immuno-fluorescence assays performed before and after labeling. A fast blood clearance was observed: 33% recovered dose (R.D.) blood level 3 h post-injection as compared with 56% after injection of control polyclonal IgG. Preliminary results on chemically induced sarcoma bearing mice showed a relatively high tumor uptake of the labeled antibody.

In vivo kinetics and thrombus accumulation of 67ga-labeled urokinase

Highly purified high and low molecular weight urokinase (H-UK and L-UK) were labeled with 67Ga using deferoxamine (DF) as a bifunctional chelating agent. The labeling efficiency was 91.7% for the H-UK, and 90.4% for the L-UK, respectively. The 67Ga labeled UK ( 67Ga-DF-UK) fully retained the enzymatic activity of the parent UK. Studies on the in vivo behavior of the 67Ga labeled UK in rabbits showed a very rapid blood clearance with half-life of 4 min ( 67Ga-DF-L-UK) to 8 min ( 67Ga-DF-H-UK Studies carried out in rabbits with induced thrombi in the femoral vein showed thrombus-to-blood 67Ga-DF-UK activity ratios, 2 h after injection, of 2.00–3.08 for the H-UK, and 0.84–1.65 for the L-UK, respectively, with thrombi aged 4 to 3 days. A dose effect of the 67Ga-DF-H-UK on its thrombus accumulation was observed. Gel chromatographic analysis of plasma samples withdrawn from those animals injected with this radiopharmaceutical revealed a reduction of the 67Ga-DF-UK effectiveness due to complexation with protein inhibitors. This led to formation of high molecular weight complexes which was reflected in the very fast blood clearance. Its implication in thrombus accumulation is discussed. In conclusion, usefulness of DF for labeling UK with 67Ga or 68Ga with no alteration of UK enzymatic properties was demonstrated. The use of 67Ga-DF-UK as a diagnostic or therapeutic radiopharmaceutical is promising.

The development and in-vivo behavior of tin containing radiopharmaceuticals—I. Chemistry, preparation, and biodistribution in small animals

Tin is an essential ingredient of most technetium-99 m radiopharmaceutical preparations but its in-vivo distribution and long-term fate are not well understood. Tin-117 m ( t 1 2 l4 d; y 159 keV, 86% ) is an ideal Tracer for studying biological behavior of tin compounds as well as for developing clinically-useful radiopharmaceuticals. This work describes the preparation and in-vivo distribution in mice of a number of tin-117 m labeled compounds with commonly used ligands. High bone uptake of most compounds studied as well as the unexpectedly high bone uptake of Sn 4+-DTPA indicates a high bone affinity of tin bound to chemically diverse ligands. Various compounds show subtle but significant differences in blood clearance, excretion, and soft-tissue uptake. Differences among Sn 2+ and Sn 4+ compounds with the same ligand are particularly noteworthy. For stannic chelates, higher bone uptake, faster blood clearance, and reduced soft-tissue concentration were observed. It appears that tin compounds bind to bone predominantly through the tin atom and that the differences in biodistribution depend on factors such as the net charge on the complex, the oxidation state of tin, and hydrolytic and kinetic stabilities of the complexes. The results indicate that the favorable half-life and decay characteristics of tin-117 m in various stannic compounds, especially stannic-DTPA, make it potentially useful as.an agent for skeletal scintigraphy and radiotherapy of bone tumors.

99mTc-imidodiphosphonate: a superior radio-pharmaceutical for in vivo positive myocardial infarct imaging. I: Experimental data.

99mTc-Imidodiphosphonate (99mTc-IDP) was investigated as an agent for nuclear medicine imaging of acute myocardial infarctions. For this purpose a suitable animal model was found. After coronary artery ligation reproducible myocardial infarcts were obtained with 80% of surviving animals. Scans of the myocardial infarcts were recorded with a high resolution gamma camera and good quality images were obtained. 99mTc-IDP ratios for normal and infarcted tissue were calculated and compared with similar data available from other 99mTc-labelled phosphates. With an infarct/normal ratio of 21:1, 99mTc-IDP is so far the best radiopharmaceutical for nuclear medicine imaging of necrosed heart muscle. Images of the myocardial infarcts have been recorded as early as 6 hours after infarction.