Abstract
Radiolabeled macrocyclic bisphosphonate ligands have recently been demonstrated to be highly efficacious in treatment of patients with painful bone metastases. Herein, we report a robust protocol for formulation of therapeutically relevant doses of 177Lu-labeled bisphosphonate amide of DOTA (BPAMD) using moderate specific activity 177Lu produced by direct (n,γ) route and its preliminary investigation in human patients. Doses (2.8 ± 0.2 GBq) were formulated with high radiochemical purity (98.3 ± 0.4 %) using a protocol optimized after extensive radiochemical studies. In vitro binding studies with mineralized osteosarcoma cells demonstrated specific binding of the radiotracer. Biodistribution studies in healthy Wistar rats demonstrated rapid skeletal accumulation with fast clearance from the non-target organs. In a patient administered with 555 MBq dose of 177Lu-BPAMD, intense radiotracer uptake was observed in the metastatic skeletal lesions with insignificant uptake in any other major non-targeted organs. Preliminary clinical investigations carried out after administration of 2.6 GBq of 177Lu-BPAMD revealed significant reduction in pain after 1 week without any adverse effects. The developed protocol for formulation of 177Lu-BPAMD doses using moderate specific activity carrier added 177Lu has been found to be effective and warrants wider investigations in patients with painful skeletal metastases.
Acknowledgements
Research at the Bhabha Atomic Research Centre is part of the ongoing activities of the Department of Atomic Energy, India and is fully supported by government funding. The authors are thankful to Dr. P. K. Pujari, Associate Director, Radiochemistry and Isotope Group, BARC, for his support and encouragement. The authors gratefully acknowledge Dr. S. V. Thakare and Mr. K. C. Jagadeesan, Radiopharmaceuticals Division, BARC, for their support in arranging the irradiation of lutetium targets.
References
1. Lange, R., Ter Heine, R., Knapp, R. F., de Klerk, J. M., Bloemendal, H. J., Hendrikse, N. H.: Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases. Bone 91, 159 (2016).10.1016/j.bone.2016.08.002Search in Google Scholar PubMed
2. Zhang, S., Gangal, G., Uludag, H.: ‘Magic bullets’ for bone diseases: progress in rational design of bone-seeking medicinal agents. Chem. Soc. Rev. 36, 507 (2007).10.1039/B512310KSearch in Google Scholar PubMed
3. de Rosales, R. T. M., Finucane, C., Mather, S. J., Blower, P. J.: Bifunctional bisphosphonate complexes for the diagnosis and therapy of bone metastases. Chem. Commun. 45, 4847 (2009).10.1039/b908652hSearch in Google Scholar PubMed PubMed Central
4. D’Oronzo, S., Coleman, R., Brown, J., Silvestris, F.: Metastatic bone disease: pathogenesis and therapeutic options update on bone metastasis management. J. Bone Oncol. 15, 100205 (2019).10.1016/j.jbo.2018.10.004Search in Google Scholar PubMed PubMed Central
5. Pfannkuchen, N., Meckel, M., Bergmann, R., Bachmann, M., Bal, C., Sathekge, M., Mohnike, W., Baum, R. P., Roesch, F.: Novel radiolabeled bisphosphonates for PET diagnosis and endoradiotherapy of bone metastases. Pharmaceuticals (Basel) 10, 45 (2017).10.3390/ph10020045Search in Google Scholar PubMed PubMed Central
6. Anderson, P., Nunez, R.: Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma. Expert. Rev. Anticancer Ther. 7, 1517 (2007).10.1586/14737140.7.11.1517Search in Google Scholar PubMed
7. Anderson, P. M., Subbiah, V., Rohren, E.: Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223. Adv. Exp. Med. Biol. 804, 291 (2014).10.1007/978-3-319-04843-7_16Search in Google Scholar PubMed
8. D’Angelo, G., Sciuto, R., Salvatori, M., Sperduti, I., Mantini, G., Maini, C. L., Mariani, G.: Targeted “bone-seeking” radiopharmaceuticals for palliative treatment of bone metastases: a systematic review and meta-analysis. Q. J. Nucl. Med. Mol. Imaging 56, 538 (2012).Search in Google Scholar
9. Bal, C., Arora, G., Kumar, P., Damle, N., Das, T., Chakraborty, S., Banerjee S, Zacnun, J. J., Pillai, M. R. A.: Pharmacokinetic, dosimetry and toxicity study of 177Lu-EDTMP in patients: phase 0/I study. Curr. Radiopharm. 9, 71 (2016).10.2174/1874471008666150313105000Search in Google Scholar PubMed
10. Bal, C., Yadav, M. P., Ballal, S.: Cocktail therapy of 177Lu-PSMA-617 and 177Lu-EDTMP in patients with mCRPC: a proof-of-principle application. Clin. Nucl. Med. 41, e386 (2016).10.1097/RLU.0000000000001251Search in Google Scholar PubMed
11. Sharma, S., Singh, B., Koul, A., Mittal, B. R.: Comparative therapeutic efficacy of 153Sm-EDTMP and 177Lu-EDTMP for bone pain palliation in patients with skeletal metastases: patients’ pain score analysis and personalized dosimetry. Front. Med. (Lausanne) 4, 46 (2017).10.3389/fmed.2017.00046Search in Google Scholar PubMed PubMed Central
12. Bergmann, R., Meckel, M., Kubicek, V., Pietzsch, J., Steinbach, J., Hermann, P., Roesch, F.: 177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment. EJNMMI Res. 6, 5 (2016).10.1186/s13550-016-0161-3Search in Google Scholar
13. Kálmán, F. K., Király, R., Brücher, E.: Stability constants and dissociation rates of the EDTMP complexes of Samarium(III) and Yttrium(III). Eur. J. Inorg. Chem. 2008, 4719 (2008).10.1002/ejic.200800582Search in Google Scholar
14. Beyer, G. J., Offord, R., Kunzi, G., Aleksandrova, Y., Ravn, U., Jahn, S., Barker, J., Tengblad, O., Lindroos, M., the ISOLDE Collaboration.: The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice. Nucl. Med. Biol. 24, 367 (1997).10.1016/S0969-8051(97)80001-7Search in Google Scholar
15. Meckel, M., Nauth, A., Timpe, J., Zhernosekov, K., Puranik, A. D., Baum, R. P., Roesch, F.: Development of a [177Lu]BPAMD labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy. Cancer Biother. Radiopharm. 30, 94 (2015).10.1089/cbr.2014.1720Search in Google Scholar PubMed
16. Chakravarty, R., Chakraborty, S., Radhakrishnan, E. R., Kamaleshwaran, K., Shinto, A., Dash, A.: Clinical 68Ga-PET: is radiosynthesis module an absolute necessity? Nucl. Med. Biol. 46, 1 (2017).10.1016/j.nucmedbio.2016.11.006Search in Google Scholar PubMed
17. Fellner, M., Biesalski, B., Bausbacher, N., Kubicek, V., Hermann, P., Roesch, F., Thews, O.: 68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter. Nucl. Med. Biol. 39, 993 (2012).10.1016/j.nucmedbio.2012.04.007Search in Google Scholar PubMed
18. Chakravarty, R., Das, T., Dash, A., Venkatesh, M.: An electro-amalgamation approach to isolate no-carrier-added 177Lu from neutron irradiated Yb for biomedical applications. Nucl. Med. Biol. 37, 811 (2010).10.1016/j.nucmedbio.2010.04.082Search in Google Scholar PubMed
19. Dash, A., Chakravarty, R., Knapp Jr, F. F., Pillai, M. R. A.: Indirect production of no carrier added (NCA) 177Lu from irradiation of enriched 176Yb: options for ytterbium/lutetium separation. Curr. Radiopharm. 8, 107 (2015).10.2174/1874471008666150312161942Search in Google Scholar PubMed
20. Chakraborty, S., Vimalnath, K. V., Lohar, S. P., Shetty, P., Dash, A.: On the practical aspects of large-scale production of 177Lu for peptide receptor radionuclide therapy using direct neutron activation of 176Lu in a medium flux research reactor: the Indian experience. J. Radioanal. Nucl. Chem. 302, 233 (2014).10.1007/s10967-014-3169-zSearch in Google Scholar
21. Chakraborty, S., Das, T., Banerjee, S., Sarma, H. D., Venkatesh, M.: Preparation and preliminary biological evaluation of 177Lu labeled hydroxyapatite as a promising agent for radiation synovectomy of small joints. Nucl. Med. Commun. 27, 661 (2006).10.1097/00006231-200608000-00008Search in Google Scholar PubMed
22. Amor-Coarasa, A., Schoendorf, M., Meckel, M., Vallabhajosula, S., Babich, J. W.: Comprehensive quality control of the ITG 68Ge/68Ga generator and synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical imaging. J. Nucl. Med. 57, 1402 (2016).10.2967/jnumed.115.171249Search in Google Scholar PubMed
23. Chakraborty, S., Chakravarty, R., Shetty, P., Vimalnath, K. V., Sen, I. B., Dash, A.: Prospects of medium specific activity 177Lu in targeted therapy of prostrate cancer using 177Lu-labeled PSMA inhibitor. J. Label. Compd. Radiopharm. 59, 364 (2016).10.1002/jlcr.3414Search in Google Scholar PubMed
24. Chakraborty, S., Goswami, D., Chakravarty, R., Mohammed, S. K., Sarma, H. D., Dash, A.: Syntheses and evaluation of 68Ga- and 153Sm- labeled DOTA-conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases. Chem. Biol. Drug Des. 92, 1618 (2018).10.1111/cbdd.13327Search in Google Scholar PubMed
25. Kumar, C., Korde, A., Kumari, K. V., Das, T., Samuel, G.: Cellular toxicity and apoptosis studies in osteocarcinoma cells, a comparison of 177Lu-EDTMP and Lu-EDTMP. Curr. Radiopharm. 6, 146 (2013).10.2174/18744710113069990021Search in Google Scholar PubMed
26. Chakraborty, S., Vimalnath, K. V., Rajeswari, A., Chakravarty, R., Sarma, H. D., Radhakrishnan, E., Kamaleshwaran, K., Shinto, A. S., Dash, A.: A ‘mix-and-use’ approach for formulation of human clinical doses of 177Lu-DOTMP at hospital radiopharmacy for management of pain arising from skeletal metastases. J. Label. Compd. Radiopharm. 60, 410 (2017).10.1002/jlcr.3517Search in Google Scholar PubMed
27. Yuan, J., Liu, C., Liu, X., Wang, Y., Dayu, K., Zhang, G., Zaknun, J. J.: 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. 38, 88 (2013).10.1097/RLU.0b013e318279bf4dSearch in Google Scholar PubMed
28. Agarwal, K. K., Singla, S., Arora, G., Bal, C. S.: 177Lu-EDTMP for palliation of pain from bone metastases in patients with prostate and breast cancer: a phase II study. Eur. J. Nucl. Med. Mol. Imaging 42, 79 (2015).10.1007/s00259-014-2862-zSearch in Google Scholar PubMed
29. Shinto, A. S., Shibu, D., Kamaleshwaran, K. K., Das, T., Chakraborty, S., Banerjee, S., Thirumalaisamy, P., Das, P.: 177Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases. J. Nucl. Med. Technol. 42, 55 (2014).10.2967/jnmt.113.132266Search in Google Scholar PubMed
30. Gleisner, K. S., Brolin, G., Sundlov, A., Mjekiqi, E., Ostlund, K., Tennvall, J., Larsson, E.: Long-term retention of 177Lu/177mLu-DOTATATE in patients investigated by γ-spectrometry and γ-camera imaging. J. Nucl. Med. 56, 976 (2015).10.2967/jnumed.115.155390Search in Google Scholar PubMed
31. Holmes, R. A., Nelson, D. H., Ketring, A. R., Corwin, L. A., Lattimer, J. C., Volkert, W. A.: Sm-153-EDTMP: evolution of a bone cancer radiopharmaceutical. J. Nucl. Med. 30, 966 (1989).Search in Google Scholar
32. Volkert, W. A., Hoffman, T. J.: Therapeutic radiopharmaceuticals. Chem. Rev. 99, 2269 (1999).10.1021/cr9804386Search in Google Scholar PubMed
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