Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that ...free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.
Objectives: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma, new effective approaches are being sought. The alpha-emitting radiopharmaceutical ...meta-211At-astato-benzylguanidine (211At-MABG) has potential as a metastatic pheochromocytoma treatment. We previously reported the tumor volume reduction effects of 211At-MABG in a PC12 pheochromocytoma mouse model. As 211At-MABG does not emit gamma-rays suitable for dosimetry and imaging, 211At-MABG needs a companion diagnostic imaging agent such as 123I-meta-iodobenzylguanidine (123I-MIBG) to be used in making treatment decisions. However, the pharmacokinetics of 123I-MIBG as a companion drug for 211At-MABG radiotherapy have not been evaluated. The purpose of this study was to evaluate the similarities and differences between 123I-MIBG and 211At-MABG in biodistribution in normal mice under clinical conditions. Methods: In this biodistribution study, male normal mice (BALB/cCrSlc, 9 weeks old) received intravenously either 997kBq of the carrier-added commercial 123I-MIBG or 483kBq of the non-carrier-added 211At-MABG. 123I-MIBG dosage was calculated based on the human clinical dose for diagnostic imaging (111MBq/60kg) on a body surface area basis, and 211At-MABG dosage was the complete remission dose identified in a PC12-xenografted mouse model. The mice were sacrificed at 1 min, 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after two tracer injections (n = 5 in each group). Blood, brain, thyroid, heart, lung, liver, spleen, stomach, small intestine, pancreas, kidney, adrenal gland, muscle, bone, urine and feces were collected, weighed and measured for radioactivity using a gamma counter. The biodistribution of two drugs was statistically compared at 6 hours post intravenous tracer injection which is the expected time to acquire images in clinical settings. Results: 211At-MABG and 123I-MIBG showed very similar biodistribution profiles in normal mice at every time point (see figure). Both drugs showed higher uptake in heart and adrenal glands. Specifically, at 6h, 123I-MIBG and 211At-MABG accumulation were similar in heart (15.5±1.5 vs. 18.1±2.8%ID/g, P=0.109) and adrenal gland (14.2±1.9 vs. 19.7±5.5%ID/g, P=0.067), respectively. 123I-MIBG showed lower uptake in lung (2.9±0.2 vs. 4.9±0.5%ID/g, P<0.0001) and liver (2.5±0.4 vs. 4.9±0.6%ID/g, P<0.0001) compared to 211At-MABG. In contrast, 123I-MIBG showed higher uptake in thyroid (0.53±0.21 vs. 0.20±0.07%ID, P=0.009) than did 211At-MABG, suggesting that dehalogenation may occur more easily in 123I-MIBG than in 211At-MABG. Total body excretion of 123I-MIBG at 24 h was higher than that of 211At-MABG (60.8±8.9% vs. 49.3±4.8%ID, P=0.033). Conclusions: At each time point, the trends for biodistribution of 123I-MIBG and 211At-MABG were almost similar in normal mice. A certain level of difference was observed in heart and adrenal gland, which have higher density of noradrenalin transporter compared to other organs. 123I-MIBG can be used for dosimetry and imaging for decisions regarding treatment with 211At-MABG radiotherapy as a companion drug. Where organs showed a difference in the estimated absorbed dose uptake of the two tracers, 123I-MIBG biodistribution data needs certain adjustments to compensate for possible under- or over-estimation of 211At-MABG absorbed dose.
To explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the
At-labeled anti-C-X-C chemokine receptor type 4 monoclonal ...antibody (
At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of
At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using
At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.
Abstract
Objectives: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma and paraganglioma (PPGL), new effective approaches are being sought. The ...radioisotope approach using 131I-meta-iodobenzylguanidine (131I-MIBG) has limited survival benefits in metastatic PPGL but is currently considered one of the standard therapeutic approaches. In theory, the alpha-emitting radiopharmaceutical meta-211At-astato-benzylguanidine (211At-MABG) could be a very effective targeted treatment for metastatic PPGL. However, this possibility has not been evaluated. Therefore, the purpose of this study was to evaluate the tumor growth suppression effects of 211At-MABG compared to 131I-MIBG using a PC-12 mouse pheochromocytoma model.
Methods: Rat pheochromocytoma (PC-12) cells were subcutaneously inoculated into male BALB/c nu/nu nude mice. When tumor volumes reached approximately 300 mm3, mice bearing PC-12 tumors received intravenously either 1.11 MBq of 211At-MABG (n=6), 31 MBq of 131I-MIBG (n=3) or vehicle solvent (n = 6). The tumor volume was measured 3 times per week for 2 weeks. The tumor volume was compared among the three groups.
Results: At 14 days, the tumor volumes significantly increased in the control group (328.82±83.65 to 3568.83±693.23 mm3, P<0.001). In contrast, there were no significant changes in tumor volumes in the 211At-MABG group (284.65±56.77 to 274.3±87.95 mm3, P=0.616) and 131I-MIBG group (484.40±46.25 to 323.93±127.27 mm3, P=0.084). The 211At-MABG group showed significantly lower percentage change in tumor volume than did the control group (-5.0±15.99 vs. 1043.83±320.79%, P<0.001), and 131I-MIBG group also showed significant volume reduction rate compared to that of the control group (-34.33±21.39 vs. 1043.82±320.79%, P<0.001). There was no significant difference in percentage tumor volume changes between the 211At-MABG and 131I-MIBG groups (P=0.052). Conclusion: At 14 days after radiopharmaceutical administration, 211At-MABG produced significant tumor volume reduction as compared to that in the control group and to that associated with 131I-MIBG, which is considered one of the current treatment options. Therefore, 211At-MABG may have future clinical applications for the treatment of metastatic pheochromocytoma and paraganglioma.
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