, Volume 3, Issue 2, pp 135–145 | Cite as

Synthesis of closo-Dodecaboryl Lipids and their Liposomal Formation for Boron Neutron Capture Therapy

  • Hiroyuki Nakamura
  • Jong-Dae Lee
  • Manabu Ueno
  • Yusuke Miyajima
  • Hyun Seung Ban


High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system to achieve a large amount of boron delivery to tumor. We succeeded in the synthesis of the double-tailed boron cluster lipids 4a–c and 5a–c, which has a B12H11S-moiety as a hydrophilic function, by S-alkylation of B12H11SH with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols. Size distribution of liposomes prepared from the boron cluster lipid 4b, dimyristoylphosphatidylcholine, polyethyleneglycol-conjugated distearoylphosphatidylethanolamine, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. Calcein-encapsulation experiments revealed that these boronated liposomes are stable at 37 °C in fetal bovine serum solution for 24 h.


closo-dodecaborate boron ion cluster lipid boron neutron capture therapy liposome mercaptoundecahydrododecaborate BSH 



This work was supported by The New Energy and Industrial Technology Development Organization (NEDO) research project of developing a hospital based accelerator for boron neutron capture therapy with advanced drug delivery system.


  1. 1.
    Locher GL. Am J Roentgenol 1936;36:632.Google Scholar
  2. 2.
    Soloway AH, Tjarks W, Barnum BA, Rong F-G, Barth RF, Codogni IM, et al. Chem Rev. 1998;98:1515–62.CrossRefGoogle Scholar
  3. 3.
    Barth RF, Soloway AH, Fairchild RG. Cancer Res 1990;50:1061–70.Google Scholar
  4. 4.
    Hawthorne MF. Angew Chem Int Ed Engl 1993;32:950–84.CrossRefGoogle Scholar
  5. 5.
    Barth RF, Soloway AH, Fairchild RG, Brugger RM. Cancer 1992;70:2995–3007.CrossRefGoogle Scholar
  6. 6.
    Soloway AH, Hatanaka H, Davis MA. J Med Chem 1967;10:714–7.CrossRefGoogle Scholar
  7. 7.
    Nakagawa Y, Hatanaka H. J Neuro-Oncol 1997;33:105–15.CrossRefGoogle Scholar
  8. 8.
    Synder HR, Reedy AJ, Lennarz WJ. J Am Chem Soc 1958;80:835–5.CrossRefGoogle Scholar
  9. 9.
    Mishima Y, Ichihashi M, Htta S, Honda C, Yamamura K, Nakagawa T. Pigment Cell Res 1989;2:226–34.CrossRefGoogle Scholar
  10. 10.
    Kato I, Ono K, Sakurai Y, Ohmae M, Maruhashi A, Imahori Y, et al. Appl Radiat Isot 2004;61:1069–73.CrossRefGoogle Scholar
  11. 11.
    Gedda L, Silvander M, Sjoberg S, Tjarks W, Carlsson J. Anti-Cancer Drug Design 1997;12:671–85.Google Scholar
  12. 12.
    Yamamoto Y, Nakamura H. J Med Chem 1993;36:2232–4.CrossRefGoogle Scholar
  13. 13.
    Yamamoto Y, Cai J, Nakamura H, Sadayori N, Asao N, Nemoto H. J Org Chem 1995;60:3352–7.CrossRefGoogle Scholar
  14. 14.
    Kelly DP, Bateman SA, Martin RF, Reum ME, Rose M, Whittaker AD. Aust J Chem 1994;47:247–62.CrossRefGoogle Scholar
  15. 15.
    Cai J, Soloway AH, Barth RF, Adams DM, Hariharan JR, Wyzlic IM, et al. J Med Chem 1997;40:3887–96.CrossRefGoogle Scholar
  16. 16.
    Nakamura H, Sekido M, Yamamoto Y. J Med Chem 1997;40:2825–30.CrossRefGoogle Scholar
  17. 17.
    Murikami H, Nagasaki T, Hamachi I, Shinkai S. Tetrahedron Lett 1993;34:6273–6.CrossRefGoogle Scholar
  18. 18.
    Kahl SB, Joel DD, Nawrocky MM, Micca PL, Tran KP, Finkel GC, et al. Proc Natl Acad Sci U S A 1990;87:7265–9.CrossRefGoogle Scholar
  19. 19.
    Miura M, Micca PL, Fisher CD, Heinrichs JC, Donaldson JA, Finkel GC, et al. Int J Cancer 1996;68:114–9.CrossRefGoogle Scholar
  20. 20.
    Woodburn K, Phadke AS, Morgan AR. Bioorg Med Chem 1993;3:2017–22.CrossRefGoogle Scholar
  21. 21.
    Kahl SB, Li J. Inorg Chem 1996;35:3878–80.CrossRefGoogle Scholar
  22. 22.
    Alam F, Soloway AH, Bapat BV, Barth RF, Adams DM. Basic Life Sci 1989;50:107–11.Google Scholar
  23. 23.
    Schinazi RF, Prusoff WH. J Org Chem 1985;50:814–7.CrossRefGoogle Scholar
  24. 24.
    Yamamoto Y, Seko T, Nemoto H. J Org Chem 1989;54:4734–6.CrossRefGoogle Scholar
  25. 25.
    Yamamoto Y, Seko T, Nakamura H, Nemoto H, Hojo H, Mukai N, et al. J Chem Soc Chem Commun. 1992;2:157–8.Google Scholar
  26. 26.
    Sood A, Shaw BR, Spielvogel BF. J Am Chem Soc 1989;111:9234–5.CrossRefGoogle Scholar
  27. 27.
    Rong F-G, Soloway AH. Nucleosides Nucleotides 1994;13:2021–34.CrossRefGoogle Scholar
  28. 28.
    Li H, Hardin C, Shaw BR. J Am Chem Soc 1996;118:6606–14.CrossRefGoogle Scholar
  29. 29.
    Malan C, Morin C. Synlett 1996;2:167–8.CrossRefGoogle Scholar
  30. 30.
    Kirihata M, Morimoto T, Ichimoto I. Biosci Biotechnol Biochem 1993;57:1940–1.CrossRefGoogle Scholar
  31. 31.
    Nakamura H, Fujiwara M, Yamamoto Y. J Org Chem 1998;63:7529–30.CrossRefGoogle Scholar
  32. 32.
    Nakamura H, Fujiwara M, Yamamoto Y. Bull Chem Soc Jpn 1998;73:231–5.CrossRefGoogle Scholar
  33. 33.
    Srivastava RR, Singhaus RR, Kabalka GW. J Org Chem 1997;62:4476–8.CrossRefGoogle Scholar
  34. 34.
    Takagaki M, Ono K, Oda Y, Kikuchi H, Nemoto H, Iwamoto S, et al. Cancer Res 1996;56:2017–20.Google Scholar
  35. 35.
    Ishiwata K, Ido T, Honda C, Kawamura M, Ishihashi M, Mishima Y. Nucl Med Biol 1992;19:311–218.Google Scholar
  36. 36.
    Radel PA, Kahl SB. J Org Chem 1996;61:4582–8.CrossRefGoogle Scholar
  37. 37.
    Kahl SB, Kasar RA. J Am Chem Soc 1996;118:1223–34.CrossRefGoogle Scholar
  38. 38.
    Prashar JK, Lama D, Moore DE. Tetrahedron Lett 1993;34:6779–82.CrossRefGoogle Scholar
  39. 39.
    Varadarajan A, Hawthorne MF. Bioconjug Chem 1991;2:242–53.CrossRefGoogle Scholar
  40. 40.
    Goldenberg DM, Sharkey RM, Primus FJ, Mizusawa EA, Hawthorne MF. Proc Natl Acad Sci U S A 1984;81:560–3.CrossRefGoogle Scholar
  41. 41.
    Alam F, Soloway AH, McGuire JE, Barth RF, Carey WE, Adams D. J Med Chem 1985;28:522–5.CrossRefGoogle Scholar
  42. 42.
    Alam F, Soloway AH, Barth RF. Antibod Immunoconjug Radiopharm 1989;2:145–63.Google Scholar
  43. 43.
    Barth RF, Alam F, Soloway AH, Adams DM, Steplewski Z. Hybridoma 1986;5:S43–50.CrossRefGoogle Scholar
  44. 44.
    Chen C-J, Kane RR, Primus FJ, Szalai G, Hawthorne MF, Shively JE. Bioconjug Chem 1994;5:557–64.CrossRefGoogle Scholar
  45. 45.
    Liu L, Barth RF, Adams DM, Soloway AH, Reisfeld RA. Anticancer Res 1996;16:2581–8.Google Scholar
  46. 46.
    Pak RH, Primus FJ, Rickard-Dickson KJ, Ng LL, Kane RR, Hawthorne MF. Proc Natl Acad Sci U S A 1995;92:6986–90.CrossRefGoogle Scholar
  47. 47.
    Andersson A, Andersson J, Burgman J-O, Capala J, Carlsson J, Conde H, et al. In: Allen BJ, Moore DE, Harrington BV, editors. Progress in neutron capture therapy for cancer. New York: Plenum; 1992. p. 41.Google Scholar
  48. 48.
    Gedda L, Olsson P, Carlsson J. Bioconjug Chem 1996;7:584–91.CrossRefGoogle Scholar
  49. 49.
    Capala J, Barth RF, Bendayan M, Lauzon M, Adams DM, Soloway AH, et al. Bioconjug Chem 1996;7:7–15.CrossRefGoogle Scholar
  50. 50.
    Yang W, Barth RF, Adams DM, Soloway AH. Cancer Res 1997;57:4333–9.Google Scholar
  51. 51.
    Cai J, Soloway AH, Barth RF, Adams DM, Hariharan JR, Wyzlic IM, et al. J Med Chem 1997;40:3887–96.CrossRefGoogle Scholar
  52. 52.
    Sood A, Shaw BR, Spielvogel BF. J Am Chem Soc 1990;112:9000–1.CrossRefGoogle Scholar
  53. 53.
    Fulcrand-El Kattan G, Lesnikowski ZJ, Yao S, Tanious F, Wilson WD, Schinazi RF. J Am Chem Soc 1994;116:7494–501.CrossRefGoogle Scholar
  54. 54.
    Kane RR, Drechsel K, Hawthorne MF. J Am Chem Soc 1993;115:8853–4.CrossRefGoogle Scholar
  55. 55.
    Nakanishi A, Guan L, Kane RR, Kasamatsu H, Hawthorne MF. Proc Natl Acad Sci U S A 1999;96:238–41.CrossRefGoogle Scholar
  56. 56.
    Klibanov A, Maruyama K, Beckerleg AM, Torchilin VP, Hung L. Biochim Biophys Acta 1991;1062:142–8.CrossRefGoogle Scholar
  57. 57.
    Maruyama K, Takizawa T, Yuda T, Kennel S, Huang L, Iwatsuru M. Biochem Biophys Acta 1995;1234:74–80.CrossRefGoogle Scholar
  58. 58.
    Maruyama K, Takahashi N, Tagawa T, Nagaike K, Iwatsuru M. FEBS Lett 1997;413:177–80.CrossRefGoogle Scholar
  59. 59.
    Maruyama K, Takizawa T, Takahashi N, Tagawa T, Nagaike K, Iwatsuru M. Adv Drug Deliv Rev 1997;24:235–42.CrossRefGoogle Scholar
  60. 60.
    Ishida O, Maruyama K, Tanahashi H, Iwatsuru M, Sasaki K, Eguchi M, et al. Pharm Res 2001;18:1042–8.CrossRefGoogle Scholar
  61. 61.
    Maruyama K, Ishida O, Kasaoka S, Takizawa T, Utoguchi N, Shinohara A, et al. J Control Release 2004;98:195–207.CrossRefGoogle Scholar
  62. 62.
    Feakes DA, Shelly K, Hawthorne MF. Proc Natl Acad Sci U S A 1995;92:1367–70.CrossRefGoogle Scholar
  63. 63.
    Watson-Clark RA, Banquerigo ML, Shelly K, Hawthorn MF, Brahn E. Proc Natl Acad Sci U S A 1998;95:2531–4.CrossRefGoogle Scholar
  64. 64.
    Nakamura H, Miyajima Y, Takei T, Kasaoka T, Maruyama K. Chem Commun 2004;17:1910–1.CrossRefGoogle Scholar
  65. 65.
    Miyajima Y, Nakamura H, Kuwata Y, Lee J-D, Masunaga S, Ono K, Maruyama K. Bioconjug Chem 2006;17:1314–20.CrossRefGoogle Scholar
  66. 66.
    Li T, Hamdi J, Hawthorne MF. Bioconjug Chem 2006;17:15–20.CrossRefGoogle Scholar
  67. 67.
    Holmberg A, Meurling L. Bioconjug Chem 1993;4:570–3.CrossRefGoogle Scholar
  68. 68.
    Swenson DH, Laster BH, Metzger RL. J Med Chem 1996;39:1540–4.CrossRefGoogle Scholar
  69. 69.
    Sano T. Bioconjug Chem 1999;10:905–11.CrossRefGoogle Scholar
  70. 70.
    Hoffmann S, Justus E, Ratajski M, Lork E, Gabel D. J Organomet Chem 2005;690:2757–60.CrossRefGoogle Scholar
  71. 71.
    Kultyshev RG, Liu J, Liu S, Tjarks W, Soloway AH, Shore SG. J Am Chem Soc 2002;124:2614–24.CrossRefGoogle Scholar
  72. 72.
    Gabel D, Moller D, Harfst S, Rosler J, Ketz H. Inorg Chem 1993;32:2276–8.CrossRefGoogle Scholar
  73. 73.
    Lee J-D, Ueno M, Miyajima Y, Nakamura H. Org Lett 2007;9:323–6.CrossRefGoogle Scholar
  74. 74.
    Nakamura H, Ueno M, Lee J-D, Ban HS, Justus E, Fan P, Gabel D. Tetrahedron Lett 2007;48:3151–4.CrossRefGoogle Scholar
  75. 75.
    Szoka F, Papahadjopoulos D. Proc Natl Acad Sci U S A 1978;75:4194–8.CrossRefGoogle Scholar
  76. 76.
    Düzgüneş N, Bagatolli LA, Meers P, Oh Y-K, Straubinger RM. In: Torchilin VP, Weissig V, editors. Liposomes. Oxford, Oxford; 2002. p. 105–19.Google Scholar
  77. 77.
    Martin SF, Josey JA, Wong Y-L, Dean DW. J Org Chem 1994;59:4805–20.Google Scholar
  78. 78.
    Speciale AJ, Smith LR. J Org Chem 1963;28:1805–11.Google Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Hiroyuki Nakamura
    • 1
  • Jong-Dae Lee
    • 1
  • Manabu Ueno
    • 1
  • Yusuke Miyajima
    • 1
  • Hyun Seung Ban
    • 1
  1. 1.Department of Chemistry, Faculty of ScienceGakushuin UniversityTokyoJapan

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