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Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent

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Abstract

In spite of recent advances in bone cellular and molecular biology, there is still a poor correlation between these parameters and data obtained from bone scintigraphy. Diphosphonate derivatives radiolabelled with technetium-99m (Tc-BPs) have long been recognised as bone-seeking agents with an affinity for areas of active mineralisation. However, during clinical trials with a pH-sensitive tumour agent, the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] showed a noticeable osteotropic character only in bone pathologies (bone metastases, Paget’s diseases) and lacked accumulation in normal mature bone. To decipher the osteotropic character of Tc(V)-DMS, a study at the cellular level was considered necessary. Moreover, to learn more about the role of Tc bone agents, acid-base regulation by bone tissue or cells was studied. First, biological parameters in body fluid were measured under systemic acidosis, induced by glucose administration, in normal and Ehrlich ascites tumour (EAT)-bearing mice. Then, in vivo biodistribution studies using Tc(V)-DMS or a conventional Tc-BP agent were carried out. The effect of glucose-mediated acidification on the skeletal distribution of the Tc agents in the mice provided valuable hints regarding the differential mediation of bone cells in skeletal tissue affinity for the agents. Thereafter, in vitro studies on osteoblast and osteoclast cells were performed and the comparative affinity of Tc(V)-DMS and Tc-BP was screened under diverse acidification conditions. Moreover, studies were also carried out on acid-base parameters related to the cellular uptake mechanism. Very specific pH-sensitive Tc(V)-DMS accumulation only in the osteoclastic system was detected, and use of Tc(V)-DMS in the differential detection of osteoblastic and osteoclastic metastases is discussed.

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Acknowledgements

We wish to express our gratitude to Drs. M. Kumegawa and Y. Hakeda from the Department of Oral Anatomy and Periontology, Mekai University School of Dentistry, Sakado, without whose help the studies on bone cells would not have been possible. We also wish to thank Nihon Mediphysics Co. Ltd, Chiba, Japan and Daichi Radioisotopes Laboratories Ltd, Chiba, Japan for providing the Tc radiopharmaceuticals. Dr. Satoshi Fukuda, from the National Institute of Radiological Sciences, Anagawa, Chiba-city, Japan, is thanked for his great help and constant support and for discussion on bone-related research.

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Authors and Affiliations

  1. Development Bureau, Hamamatsu Photonics K.K., Hirakuchi 500, 434-8601, Hamakita City, Japan

    Kazuko Horiuchi-Suzuki

  2. Department of Radioisotope Production, Japan Energy Research Institute, Ibaraki-ken, Tokai-mura, Japan

    Kazuyuki Hashimoto

  3. Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Aya Konno, Mayumi Ueda, Yoko Fukuda, Saori Nishio & Hideo Saji

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  1. Kazuko Horiuchi-Suzuki
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  2. Aya Konno
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  3. Mayumi Ueda
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  6. Kazuyuki Hashimoto
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Correspondence to Kazuko Horiuchi-Suzuki.

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Ueda Mayumi has sadly died since the completion of this article. Requiescat in pace.

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Horiuchi-Suzuki, K., Konno, A., Ueda, M. et al. Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent. Eur J Nucl Med Mol Imaging 31, 388–398 (2004). https://doi.org/10.1007/s00259-003-1364-1

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  • DOI: https://doi.org/10.1007/s00259-003-1364-1

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