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Journal of Neuro-Oncology

, Volume 103, Issue 2, pp 175–185 | Cite as

Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors

  • Shinji Kawabata
  • Weilian Yang
  • Rolf F. Barth
  • Gong Wu
  • Tianyao Huo
  • Peter J. Binns
  • Kent J. Riley
  • Owendi Ongayi
  • Vijay Gottumukkala
  • M. Graça H. Vicente
Laboratory Investigation - Human/Animal Tissue

Abstract

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α]7Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by Alzet™ osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) ± standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 ± 4 and 44 ± 10 days, compared to 23 ± 3 and 27 ± 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3–5× higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be used as delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of synthesizing and evaluating carboranylporphyrins that could have enhanced cellular uptake and improved therapeutic efficacy.

Keywords

Convection enhanced delivery Carboranylporphyrins Boron neutron capture therapy F98 rat glioma 

Notes

Acknowledgments

This paper is dedicated to Professor Otto Harling in recognition of his outstanding contributions to the field of BNCT research, and more specifically to his vision and foresight that made the Massachusetts Institute of Technology Research Reactor one of the leading facilities in the world to carry out BNCT studies. Sadly, such studies are no longer being carried out at this facility. We thank Ms. Michelle Van Fossen for expert secretarial assistance in the preparation of this manuscript and Dr. Michael Pennell, Division of Biostatistics, OSU, College of Public Health, for his helpful comments relating to statistical evaluation of the data. The studies described in this report were supported by N.I.H. grants R01 CA098902 (M.G.H.V.) and R01 CA098945 (R.F.B.), and the United States Department of Energy through the program of Innovations in Nuclear Infrastructure and Education, Office of Nuclear Energy, Science and Technology (contract no. DE-FG07-02ID14420DE-FG07-02, K14420), and the Office of Environmental and Biological Research (contract no. DE-FG02-02ER63358) (K.J.R. and P.J.B.). One of US (RFB) gratefully acknowledges support of The Ohio State University Department of Pathology for partial funding of the final stages of this study.

Conflicts of interest

There are no conflicts of interest.

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Shinji Kawabata
    • 4
  • Weilian Yang
    • 1
  • Rolf F. Barth
    • 1
  • Gong Wu
    • 1
  • Tianyao Huo
    • 1
  • Peter J. Binns
    • 2
    • 5
  • Kent J. Riley
    • 2
    • 6
  • Owendi Ongayi
    • 3
  • Vijay Gottumukkala
    • 3
  • M. Graça H. Vicente
    • 3
  1. 1.Department of PathologyThe Ohio State UniversityColumbusUSA
  2. 2.Nuclear Reactor Laboratory, Massachusetts Institute of TechnologyCambridgeUSA
  3. 3.Department of ChemistryLouisiana State UniversityBaton RougeUSA
  4. 4.Department of NeurosurgeryOsaka Medical CollegeTakatsuki CityJapan
  5. 5.Department of Radiation OncologyMount Auburn HospitalCambridgeUSA
  6. 6.Radiation Monitoring Devices, IncWatertownUSA

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