Skip to main content
SpringerLink
Log in

Targeted Drug Delivery for Boron Neutron Capture Therapy

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT.

Methods. Strategies that involve synthetic chemical approaches and biochemical and biophysical approaches are employed to meet this requirement. Compounds developed for targeting to tumors include borocaptate sodium (BSH) and p-boronophenylalanine (BPA) which are currently in clinical use.

Results. Boronated porphyrins, nucleosides, nucleotides and other boronated compounds show potentials as targeting molecules. Conjugation of boron compounds to macromolecules such as monoclonal antibodies, epidermal growth factor and dextran is also employed for active or passive tumor targeting.

Conclusions. Boron delivery via microparticulate carriers such as liposomes, high density lipoproteins and microcapsules is also attractive for its potential application in BNCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. R. F. Barth, A. H. Soloway, R. G. Fairchild, and R. M. Brugger. Boron neutron capture therapy for cancer. Cancer 70:2995–3007 (1992).

    Google Scholar 

  2. A. H. Soloway, R. F. Barth and D. E. Carpenter. Advances in Neutron Capture Therapy, Plenum Press, New York, 1993.

    Google Scholar 

  3. B. Allen, D. Moore, and B. Harrington. Progress in Neutron Capture Therapy for Cancer, Plenum Press, New York, 1992.

    Google Scholar 

  4. J. Carlsson, S. Sjoberg, and B. S. Larsson. Present status of boron neutron capture therapy. Acta Oncol. 31(8):803–813 (1992).

    Google Scholar 

  5. R. F. Barth, A. H. Soloway, and R. G. Fairchild. Boron neutron capture therapy for cancer. Cancer Res. 50:1061–1070 (1990).

    Google Scholar 

  6. L. Dewit, R. Moss, and D. Gabel. New Developments in Neutron Capture Therapy. Eur. J. Cancer 26(8):912–914 (1990).

    Google Scholar 

  7. A. K. Asbury, R. G. Ojeann, S. L. Nielsen, and W. H. Sweet. Neuropathologic study of fourteen cases of malignant brain tumor treated by boron-10 slow neutron capture radiation. J. Neuropathol. Exp. Neurol. 31:278–303 (1972).

    Google Scholar 

  8. H. Hatanaka and Y. Nakagawa. Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy. Int. J. Radiat. Oncol. Biol. Phys. 28(5):1061–1066 (1994).

    Google Scholar 

  9. F. Flam. Boron therapy gets early test. Science 265(5180):1799 (1994).

    Google Scholar 

  10. A. H. Soloway, H. Hatanaka, and M. A. Davis. Penetration of brain and brain tumor. VII. Tumor-binding sulfhydryl boron compounds. J. Med. Chem. 10:714–717 (1967).

    Google Scholar 

  11. M. Abe, K. Kitamura, K. Amano, and H. Hatanaka. Boron-10-mercaptoundecahydrododecaborate distribution in rat brain tumors. In H. Hatanaka (Ed.), Boron Neutron Capture Therapy for Tumors, Nishimura Co. Ltd., Niigata, Japan, 1986, pp. 117–124.

    Google Scholar 

  12. H. Hatanaka, K. Amano, H. Kanemitsu, I. Ikeuchi, and T. Yoshizaki. Boron uptake by human brain tumors and quality control of boron compounds. In H. Hatanaka (ed.), Boron Neutron Capture Therapy for Tumors, Chap. 5, Nishimura Co. Ltd., Niigata, Japan, 1986, pp. 77–106.

    Google Scholar 

  13. D. Gabel. Present status and perspectives of boron neutron capture therapy. Radiother. Oncol. 30:199–205 (1994).

    Google Scholar 

  14. S. L. Kraft, P. R. Gavin, C. E. DeHann, C. W. Leathers, W. F. Bauer, D. L. Miller, and R. V. Dorn III. Borocaptate sodium—a potential boron delivery compound for boron neutron capture therapy evaluated in dogs with spontaneous intracranial tumors. Proc. Natl. Acad. Sci. 89:11973–11977 (1992).

    Google Scholar 

  15. D. Slatkin, P. Micca, A. Forman, D. Gabel, L. Weilopolski, R. Fairchild. Boron uptake in melanoma, cerebrum and blood from Na2B12H11SH and Na4B24H22S2 administered to mice. Biochem. Pharmacol. 35(10):1771–1776 (1986).

    Google Scholar 

  16. S. C. Mehta, F. D. Boudinot, and D. R. Lu. Pharmacokinetics of sodium mercaptoundecahydrododecaborate (BSH) after intravenous injection in rats. Drug Metabol. Disp. 23(12):1368–1371 (1995).

    Google Scholar 

  17. S. C. Mehta and D. R. Lu. Interspecies pharmacokinetic scaling of BSH in mice, rats rabbits and humans. Biopharmaceutics and Drug Disposition 16:735–744 (1995).

    Google Scholar 

  18. P. G. Marshall, M. E. Miller, S. Grand, P. G. Micca, and D. N. Slatkin. Toxicities of Na2B12H11SH and Na4B24H22S2 in mice. In R. G. Fairchild, V. P. Bond, and A. D. Woodhead (eds.), Clinical Aspects of Neutron Capture Therapy, Plenum Press, New York, 1989, pp. 333–351.

    Google Scholar 

  19. D. N. Slatkin, P. L. Micca, B. H. Laster, and R. G. Fairchild. Distribution of sulfhydryl boranes in mice and rats. In R. F. Fairchild and V. P. Bond (eds.), Workshop on neutron capture therapy, Brookhaven National Laboratory-51994, Upton, 1986, pp. 173–176.

    Google Scholar 

  20. M. Miura, P. Micca, J. Heinrichs, and D. Slatkin. Synthesis and preliminary in vivo toxicity evaluation of an iodinated sulfidoborate. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 339–343.

    Google Scholar 

  21. Y. Mishima, C. Honda, M. Ichihashi, H. Obara, J. Hiratsuka, H. Fukuda, H. Karashima, T. Kobayashi, K. Kanda, and K. Yoshino. First cure of primary malignant melanoma in man by single thermal neutron capture therapy using melanoma-seeking 10B-compound. Lancet. II:388–389 (1989).

    Google Scholar 

  22. J. A. Coderre, J. A. Kalef-Ezra, R. G. Fairchild, P. L. Micca, L. E. Reinstein, and J. D. Glass. Boron neutron capture therapy of a murine melanoma. Cancer Res. 48:6313–6316 (1988).

    Google Scholar 

  23. J. A. Coderre, J. D. Glass, R. G. Fairchild, P. L. Micca, I. Fand, and D. Joel. Selective delivery of boron by the melanin precursor analogue p-boronophenylalanine to tumors other than melanoma. Cancer Res. 50:138–141 (1990).

    Google Scholar 

  24. T. LaHann, C. Sills, G. Hematillake, T. Dymock, and G. Daniell. Cardiovascular toxicities associated with intravenous administration of p-Boronophenylalanine formulations. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 513–517.

    Google Scholar 

  25. T. LaHann, W. F. Bauer, and D. R. Lu. Pharmacokinetics of boronophenylalanine delivered in HP-β-cyclodextrin formulation. In R. M. Ottenbrite (ed.), Polymeric Drugs and Drug Delivery Systems, ACS Book Series 545, American Chemical Society, Washington, DC, 1994, pp. 66–78.

    Google Scholar 

  26. K. Yoshino, T. Maruyama, Y. Mori, H. Kakihana, and Y. Mishima. Capture of p-boronophenylalanine by melanin-related compounds: complex formation of p-boronophenylalanine with L-DOPA. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 249–252.

    Google Scholar 

  27. J. L. Mallesch, D. E. Moore, B. J. Allen, W. H. MacCarthy, R. Jones, and W. A. Stening. The pharmacokinetics of p-boronophenylalanine fructose in human patients with glioma and metastatic melanoma. Int. J. Radiat. Oncol. Biol. Phys. 28(5):1183–1188 (1994).

    Google Scholar 

  28. T. R. LaHann, D. R. Lu, G. Daniell, C. Sills, S. L. Kraft, P. R. Gavin, and W. F. Bauer. Bioavailability of intravenous formulations of p-Borophenylalanine in dog and rat. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 585–589.

    Google Scholar 

  29. I. Wyzlic, A. Soloway, R. Barth, and J. Rotaru. Synthesis and evaluation of carborane-containing amino acids for boron neutron capture therapy. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 281–284.

    Google Scholar 

  30. J. S. Hill, S. B. Kahl, A. H. Kaye, S. S. Stylli, M. S. Koo, M. F. Gonzales, N. J. Vardaxis, and C. I. Johnson. Selective tumor uptake of a boronated porphyrin in an animal model of cerebral glioma. Proc. Natl. Acad. Sci. USA 89(5):1785–1789 (1992).

    Google Scholar 

  31. L. R. Huang, R. Straubinger, S. B. Kahl, M. S. Koo, J. J. Alletto, R. Mazurchuk, R. I. Chau, S. L. Thamer, and R. J. Fiel. Boronated metalloporphyrins: a novel approach to the diagnosis and treatment of cancer using contrast-enhanced MR imaging and neutron capture therapy. J. Magn. Reson. Imaging. 3(2):351–356 (1993).

    Google Scholar 

  32. R. F. Schinazi and W. H. Prusoff. Synthesis and properties of boron and silicon substituted uracil or 2′-deoxyuridine. Tetrahedr. Lett. 50:4981–4984 (1978).

    Google Scholar 

  33. R. F. Schinazi, N. M. Goudgaon, G. Fulcrand, Y. el-Kattan, Z. Lesnikowski, G. Ullas, J. Moravek, and D. C. Liotta. Cellular pharmacology and biological activity of 5-carboranyl-2′-deoxyuridine. Int. J. Radiat. Oncol. Biol. Phys. 28(5):1113–1120 (1994).

    Google Scholar 

  34. B. Spielvogel, A. Sood, W. Powell, J. Tomasz, K. Porter, and B. Shaw. Chemical and enzymatic incorporation of boron into DNA. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 389–393.

    Google Scholar 

  35. P. Lemmen, B. Werner, and B. Streicher. Ether lipids as potential boron carriers for boron neutron capture therapy: synthesis of rac-1-(9-o-carboranyl)nonyl-2-methyl-glycero-3-phosphocholine (B-Et-11-OMe). In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 297–300.

    Google Scholar 

  36. Y. Yamamoto, H. Nakamura, and H. Nemoto. Synthesis and biological properties of carboranylaziridine. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 305–308.

    Google Scholar 

  37. J. Livesey, L. Wiens, D. Wilbur, D. Hamlin, and G. Laramore. Hypoxia-selective cellular toxicity of carboranyl nitroimidazole. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 315–318.

    Google Scholar 

  38. A. Corder, A. Whittaker, D. Kelly, H. Meriaty, B. Allen, and R. Martin. Evaluation of 10B-labelled DNA ligand. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 377–381.

    Google Scholar 

  39. S. Novick, M. Quastel, S. Marcus, D. Chipman, G. Shani, R. Barth, and A. Soloway. Binding of boronated polylysine to immunoglobulin by way of glycoside moieties: Immunoreactivity and boron content. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 357–360.

    Google Scholar 

  40. R. F. Barth, D. M. Adams, A. H. Soloway, and M. Darby. In vivo distribution of boronated monoclonal antibodies and starburst dendrimers. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 351–355.

    Google Scholar 

  41. J. Capala, R. F. Barth, D. M. Adams, A. H. Soloway, and J. Carlsson. Epidermal growth factor as a potential targeting agent for delivery of 10B to malignant gliomas. In A. H. Soloway, R. F. Barth, and D. E. Carpenter (eds.), Advances in Neutron Capture Therapy, Plenum Press, New York, 1993, pp. 371–375.

    Google Scholar 

  42. A. Holmberg and L. Meurling. Preparation of sulfhydrylborane-dextran conjugates for boron neutron capture therapy. Bioconjugate Chem. 4:570–573 (1993).

    Google Scholar 

  43. G. Gregoriadis and A. T. Florence. Liposomes in drug delivery: Clinical, diagnostic and ophthalmic potential. Drugs 45(1): 15–28 (1993).

    Google Scholar 

  44. K. Shelly, D. A. Feaks, M. F. Hawthrone, P. G. Schmidt, T. A. Krisch, and W. F. Bauer. Model studies directed toward the boron neutron-capture therapy of cancer: Boron delivery to murine tumors with liposomes. Proc. Natl. Acad. Sci. USA 89:9039–43 (1992).

    Google Scholar 

  45. D. A. Feaks, K. Shelly, C. B. Knobler, and M. F. Hawthrone. Na3[B20H17NH3]: Synthesis and liposomal delivery to murine tumors. Proc. Natl. Acad. Sci. USA 91:3029–3033 (1994).

    Google Scholar 

  46. S. C. Mehta, J. C. K. Lai, and D. R. Lu. Liposomal formulations containing sodium mercaptoundecahydrododecaborate (BSH) for boron neutron capture therapy. J. Microencapsul. (In press) (1995).

  47. H. Yanagie, T. Tomita, H. Kobayashi, Y. Fujii, T. Takahashi, K. Hasumi, H. Nariuchi, and M. Sekiguchi. Application of boronated anti-CEA immunoliposomes to tumor cell growth inhibition in in vitro boron neutron capture therapy model. Br. J. Cancer 63:522–526 (1991).

    Google Scholar 

  48. B. H. Laster, S. B. Kahl, E. A. Popenoe, D. W. Pate, and R. G. Fairchild. Biological efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture. Cancer Res. 51:4588–4593 (1992).

    Google Scholar 

  49. Y. Akine, N. Tokita, K. Tokuuye, M. Satoh, Y. Fukumori, H. Tokumitsu, R. Kanamori, T. Kobayashi, and K. Kanda. Neutron capture therapy of murine ascites tumor with gadolinium-containing microcapsules. J. Cancer Res. Clin. Oncol. 119:71–73 (1992).

    Google Scholar 

  50. S. Mehta, J. Olson, and D. R. Lu. Brain tissue reaction following intracerebral injection of free or liposomally encapsulated BSH. Drug Delivery (In press) (1995).

Download references

Author information

Author notes

  1. Samir C. Mehta

    Present address: College of Pharmacy, University of Utah, Salt Lake City, Utah, 84112

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens, Georgia, 30602

    Samir C. Mehta & D. Robert Lu

Authors
  1. Samir C. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Robert Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mehta, S.C., Lu, D.R. Targeted Drug Delivery for Boron Neutron Capture Therapy. Pharm Res 13, 344–351 (1996). https://doi.org/10.1023/A:1016076022267

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016076022267

Search

Navigation