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EJNMMI Research
Published in: EJNMMI Research 1/2016

Open Access 01-12-2016 | Original research

177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment

Authors: Ralf Bergmann, Marian Meckel, Vojtěch Kubíček, Jens Pietzsch, Jörg Steinbach, Petr Hermann, Frank Rösch

Published in: EJNMMI Research | Issue 1/2016

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Abstract

Background

Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. No-carrier-added (n.c.a.) 177Lu is remarkably suitable for an application in this scope.

Methods

Five 1,4,7,10-tetraazacyclododecane N,N′,N′′,N′′-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. 177Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [177Lu]citrate.

Results

Radiolabelling yields for [177Lu]Lu-DOTA and [177Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All 177Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. 177Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [177Lu]Lu-DO2A(PBP)2; SUVfemur = 5.41 ± 0.46 for [177Lu]Lu-DOTA(MBP)2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [177Lu]Lu-DO2A(PBP)2; SUVblood = 1.43 ± 0.32 for [177Lu]Lu-DOTA(MBP)2).

Conclusions

Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.
Literature
1.
Sartor O, Hoskin P, Bruland OS. Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev. 2013;39:18–26.PubMedCrossRef
2.
Kutzner J, Grimm W, Hahn K. Palliative radiotherapy with Strontium-89 in case of extended formation of skeleton metastases. Struct Bond (Berlin). 1978;154:317–22.
3.
Zenda S, Nakagami Y, Toshima M, Arahira S, Kawashima M, Matsumoto Y, et al. Strontium-89 (Sr-89) chloride in the treatment of various cancer patients with multiple bone metastases. Int J Clin Oncol. 2013;19(4):739–43.PubMedCrossRef
4.
Williams MH, Hamilton JG, Johnston ME, Asing CW, Durbin PW. The metabolism of the lanthanons in the rat. II. Time studies of the tissue deposition of intravenously administered radioisotopes. USAEC Report. 1956;12(J.G. Hamilton):171.
5.
O’Mara RE, McAfee JG, Subramanian G. Rare earth nuclides as potential agents for skeletal imaging. J Nucl Med. 1968;10:49–51.
6.
Lutetium-177: handling precautions, 2010, Perkin-Elmer Inc. www.perkinelmer.com.
7.
Tomassetti P, Falconi M, Delle Fave G, Cacciari G, Tamburrino D, Pantuzo F, et al. Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence. EJMMI. 2013;40(8):1197–205.
8.
Yuan J, Lui C, Liu X, Wang Y, Kuai D, Zhang G, et al. Efficacy and safety of 177Lu-EDTMP in bone metastatic pain palliation in breast cancer and hormone refractory prostate cancer: a phase II study. Clin Nucl Med. 2013;38(2):88–92.PubMedCrossRef
9.
Chakraborty S, Das T, Unni PR, Sarma HD, Samuel G, Banerjee S, et al. 177Lu labelled polyaminophosphonates as potential agents for bone pain palliation. Nucl Med Comm. 2002;23:67–74.CrossRef
10.
F. K. Kalman, R. Kiraly, E. Brücher, Stability constants and dissociation rates of the EDTMP complexes of Samarium(III) and Yttrium(III), Eur J Inorg Chem; 2008;30:4719–4727
11.
Beyer BJ, Offord R, Künzi G, Aleksandrova Y, Ravn U, Jahn S, et al. The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice. Nucl Med & Biol. 1997;24:367–72.CrossRef
12.
Byegård J, Skarnemark G, Skalberg M. The stability of some metal EDTADTPA and DOTA complexes: application as tracers in groundwater studies. J Radioanal & Nucl Chem. 1999;241:281–90.CrossRef
13.
Smentek L. Lanthanides caged by the organic chelates; structural properties. J Phys Condens Matter. 2011;23:143202.PubMedCrossRef
14.
Chakrabotry S, Das T, Sarma HD, Venkatesh M, Banerjee S. Comparative studies of 177Lu–EDTMP and 177Lu–DOTMP as potential agents for palliative radiotherapy of bone metastasis. Appl Radiat Isot. 2008;66:1196–205.CrossRef
15.
Kletter K, Dudczak R, Kluger R, Viernstein H, Ettlinger DE, Eidherr H, et al. Pre vivo, ex vivo and in vivo evaluations of [68Ga]-EDTMP. Nucl Med & Biol. 2007;34:391–7.CrossRef
16.
Fellner M, Riss P, Loktionova N, Zhernosekov K, Thews O, Geraldes CFGC, et al. Comparison of different phosphorus-containing ligands complexing 68Ga for PET-imaging of bone metabolism. Radiochim Acta. 2011;99:43–51.CrossRef
17.
Fellner M, Biesalski B, Bausbacher N, Kubicek V, Hermann P, Rösch F, et al. 68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter. Nucl Med & Biol. 2012;39:993–9.CrossRef
18.
Vitha T, Kubicek V, Hermann P, Elst LV, Mueller RN, Kolar ZI, et al. Lanthanide(III) complexes of bis(phosphonate) monoamide analogues of DOTA: bone-seeking agents for imaging and therapy. J Med Chem. 2008;51:677–83.PubMedCrossRef
19.
20.
Fellner M, Baum RP, Kubicek V, Herrman P, Lukes I, Prasad V, et al. PET/CT imaging of osteoblastic bone metastases with 68Ga-bisphosphonates: first human study. EJNMMI. 2010;37:834.
21.
Holub J, Meckel M, Kubicek V, Rösch F, Hermann P. Gallium(III) complexes of NOTA-bis(phosphonate) conjugates as radiotracers for bone imaging. CMMI. 2015;10(2):122–34.PubMed
22.
Meckel M, Fellner M, Thieme N, Bergmann R, Kubicek V, Rösch F. In vivo comparison of DOTA based 68Ga-labelled bisphosphonates for bone imaging in non-tumour models. Nucl Med & Biol. 2013;40:823–30.CrossRef
23.
Ogawa K, Takai K, Kanbara H, Kiwada T, Kitamura Y, Shiba K, et al. Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent. Nucl Med & Biol. 2011;38:631–6.CrossRef
24.
Vitha T, Kubicek V, Hermann P, Kolar ZI, Wolterbeek HT, Peters JA, et al. Complexes of DOTA-bisphosphonate conjugates: probes for determination of adsorption capacity and affinity constants of hydroxyapatite. Langmuir. 2008;24:1952–8.PubMedCrossRef
25.
Rösch F, Brockmann J, Misiak R, Novgorodov AF, Lebedev NA. Radiochemical separation of no-carrier-added 177Lu as produced via the 176Yb(n,γ)177Yb®177Lu process. Appl Radiat Isot. 2000;53:421–5.PubMedCrossRef
26.
Riss PJ, Burchardt C, Rösch F. A methodical 68Ga‐labelling study of DO2A‐(butyl‐L‐tyrosine) 2 with cation‐exchanger post-processed 68Ga: practical aspects of radiolabelling. CMMI. 2011;6:492–8.PubMed
27.
Kubicek V, Rudovsky J, Kotek J, Hermann P, Elst LV, Mueller RN, et al. A bisphosphonate monoamide analogue of DOTA: a potential agent for bone targeting. J Am Chem Soc. 2005;127:16477–85.PubMedCrossRef
28.
Peters JA, Lukes I, Mueller RN, Elst LV, Hermann P, Kotek J, et al. Gd(III) complex of a monophosphinate-bis(phosphonate) DOTA analogue with a high relaxivity; lanthanide(III) complexes for imaging and radiotherapy of calcified tissues. Dalton Trans. 2009;17:3204–14.PubMed
29.
Sontag W. Long-term behavior of 239Pu, 241Am and 233U in different bones of one-year-old rats: macrodistribution and macrodosimetry. Human Toxicol. 1984;3:69–483.
Metadata
Title
177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment
Authors
Ralf Bergmann
Marian Meckel
Vojtěch Kubíček
Jens Pietzsch
Jörg Steinbach
Petr Hermann
Frank Rösch
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-016-0161-3

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