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Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98EGFR. EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.t.) injection or intracerebral (i.c.) convection enhanced delivery (CED) of 125I-labeled or unlabeled BD-EGF (40 μg 10B/10 μg EGF) to F98 glioma bearing rats. At 24 h. there was 43% more radioactivity in EGFR(+) tumors following CED compared to i.t. injection, and a doubling of the tumor boron concentration (22.3 μg/g vs. 11.7 μg/g). CED of BD-EGF resulted in a 7.2× increase in the volume of distribution within the infused cerebral hemisphere and a 1.9× increase in tumor uptake of BD-EGF compared with i.t. injection. Based on these favorable biodistribution data, BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following i.c. tumor implantation and 24 h. after CED of BD-EGF. These animals had a MST of 54.1 ± 4.7 days compared to 43.0 ± 2.8 days following i.t. injection. Rats that received BD-EGF by CED in combination with i.v. boronophenylalanine (BPA), which has been used in both experimental and clinical studies, had a MST of 86.0 ± 28.1 days compared to 39.8 ± 1.6 days for i.v. BPA alone (P < 0.01), 30.9 ± 1.4 days for irradiated controls and 25.1 ± 1.0 days for untreated controls (overall P < 0.0001). These data have demonstrated that the efficacy of BNCT was significantly increased (P < 0.006), following i.c CED of BD-EGF compared to i.t injection, and that the survival data were equivalent to those previously reported by us using the boronated anti-human-EGF mAb, C225 (cetuximab).

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Acknowledgements

We thank Ms. Michelle Van Fossen for secretarial assistance in the preparation of this manuscript. The studies described in this report were supported by N.I.H. grants 1R01 CA098945 (R.F. Barth), the Roswell Park Alliance Foundation (R.A. Fenstermaker), and the United States Department of Energy thorugh 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).

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Author notes

  1. Peter J. Binns

    Present address: Department of Radiology, Mount Auburn Hospital, Cambridge, MA, USA

  2. Kent J. Riley

    Present address: Radiation Monitoring Devices, Inc, Watertown, MA, 02172, USA

Authors and Affiliations

  1. Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA

    Weilian Yang, Rolf F. Barth, Gong Wu & Tianyao Huo

  2. Colleges of Pharmacy, The Ohio State University, Columbus, OH, USA

    Werner Tjarks

  3. Department of Neurosurgery, Roswell Park Memorial Institute, Buffalo, NY, USA

    Michael Ciesielski & Robert A. Fenstermaker

  4. Department of Radiology, University of Michigan, Ann Arbor, MI, USA

    Brain D. Ross

  5. Department of Microbiology, Saba University School of Medicine, Saba, Netherlands Antilles

    Carol J. Wikstrand

  6. The Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA

    Kent J. Riley & Peter J. Binns

  7. Department of Pathology, Duke University, Durham, NC, USA

    Carol J. Wikstrand

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Yang, W., Barth, R.F., Wu, G. et al. Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors. J Neurooncol 95, 355–365 (2009). https://doi.org/10.1007/s11060-009-9945-x

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